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1. Figure S15 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Primary clustering of tumor cells and immune cell populations

Published
2023

2. Table S2 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

MAGeCK analysis of CRISPR screen

Published
2023

3. Figure S4 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Loss of Asf1a shows no significant effect on DNA damage and tumor cell proliferation

Published
2023

4. Figure S5 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Asf1a knockdown combined with anti-PD-1 therapy shows significant inhibition of tumor growth

Published
2023

5. Figure S9 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Asf1a KO and anti-PD-1 combination therapy primes and activates T cells that can recognize specific tumor-associated antigen

Published
2023

6. Figure S17 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Secondary clustering of T cells

Published
2023

7. Figure S7 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Gating strategy for immune profile analyses in this study

Published
2023

8. Figure S13 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Macrophages pre-cultured with Asf1a KO tumor cells show potential effect to activate T cells

Published
2023

9. Figure S14 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

In vivo F4/80 or GM-CSF blockade attenuates anti-tumor immune response in Asf1a KO and anti-PD-1 combination therapy

Published
2023

10. Figure S1 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Library and cells used for in vivo CRISPR screen

Published
2023

11. Figure S11 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Luminex analysis of chemokine/cytokine secretions

Published
2023

12. Table S1 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Reads count of CRISPR screen

Published
2023

13. Figure S6 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Asf1a KO synergizes with anti-PD-1 to inhibit tumor progression in multiple models

Published
2023

14. Figure S10 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Alterations of myeloid populations in an orthotopic KP lung tumor model with short-term treatment

Published
2023

15. Figure S2 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Quality controls performed to validate the in vivo screening platform

Published
2023

16. Figure S16 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Secondary clustering of macrophages/monocytes

Published
2023

17. Figure S8 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Alterations of T cell populations in an orthotopic KP lung tumor model with short-term treatment

Published
2023

18. Figure S3 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

CRISPR screen to identify targets regulating the natural host antitumor response

Published
2023

19. Table S3 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Enriched gene sets in ASF1A-low tumors and Asf1a KO cells

Published
2023

20. Data from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses—such as epigenetic modulation of antitumor immunity—is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an in vivo CRISPR screen in a KrasG12D/Trp53−/− LUAD model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti–PD-1 treatment. Mechanistic studies revealed that tumor cell–intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti–PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti–PD-1 immunotherapy.Significance:Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti–PD-1 therapy. Asf1a deficiency synergized with anti–PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.See related commentary by Menzel and Black, p. 179.This article is highlighted in the In This Issue feature, p. 161

Published
2023

21. Figure S12 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

ATAC-seq in KP cells and the up-regulation of CSF2 by ASF1A knockdown in H2009 cells

Published
2023

22. Table S2 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han

Abstract

GSEA analysis of mobocertinib and T-DM1 treated tumors versus mobocertinib-only treated tumors Genes involved in "INTERFERON ALPHA RESPONSE", "INFLAMMATORY RESPONSE", "INTERFERON GAMMA RESPONSE", "IL2 STAT5 SIGNALING", "TNFA SIGNALING VIA NFKB" and "IL6 JAK STAT3 SIGNALING" pathways of HALLMARK gene sets.

Published
2023

23. Data from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han

Abstract

No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients.Significance:This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Published
2023

24. Table S1 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han

Abstract

GSEA analysis of mobocertinib acquired resistant tumors versus response tumors Genes involved in "G2M CHECKPOINT", "MITOTIC SPINDLE" and "MTORC1 SIGNALING" pathways of HALLMARK gene sets.

Published
2023

25. Figure S1 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han

Abstract

Figure S1

Published
2023

26. Figure S2 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han

Abstract

Figure S2

Published
2023

27. Figure S3 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han

Abstract

Figure S3

Published
2023

28. Figure S4 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han

Abstract

Figure S4

Published
2023

29. Table S2 from Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

Author

Kwok-Kin Wong, Jun Qi, Richard Possemato, George Miller, John T. Poirier, Christina Almonte, Kristen Labbe, Yuanwang Pan, Shuai Li, Val Pyon, Angeliki Karatza, Mousheng Xu, Alireza Khodadadi-Jamayran, Hon-Cheong So, Kai Zhao, Jiehui Deng, Ting Chen, Zhaoyuan Fang, Wei Wang, Michela Ranieri, Qingyuan Huang, Hua Zhang, Paula Zouitine, Kate E.R. Hollinshead, Catríona M. Dowling, Vladislav O. Sviderskiy, Hai Hu, Troy A. Luster, Wai-Lung Ng, and Fei Li

Abstract

Candidate lists for CRISPR screens

Published
2023

30. Table S4 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai

Abstract

qRT-PCR primer sequences

Published
2023

31. Data from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai

Abstract

Purpose:Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed.Experimental Design:We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines.Results:We show that multiplex gene editing of mouse lung organoids using the CRISPR–Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell–mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti–PD-1 therapy.Conclusions:We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage–inducing therapies in the treatment of LSCC.

Published
2023

32. Table S2 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai

Abstract

CRISPR/Cas9 guides, primers and sequencing results

Published
2023

33. Table S3 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai

Abstract

Antibodies used for Immunohistochemistry, Immunofluroesence and immunblotting

Published
2023

34. Data from Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

Author

Kwok-Kin Wong, Jun Qi, Richard Possemato, George Miller, John T. Poirier, Christina Almonte, Kristen Labbe, Yuanwang Pan, Shuai Li, Val Pyon, Angeliki Karatza, Mousheng Xu, Alireza Khodadadi-Jamayran, Hon-Cheong So, Kai Zhao, Jiehui Deng, Ting Chen, Zhaoyuan Fang, Wei Wang, Michela Ranieri, Qingyuan Huang, Hua Zhang, Paula Zouitine, Kate E.R. Hollinshead, Catríona M. Dowling, Vladislav O. Sviderskiy, Hai Hu, Troy A. Luster, Wai-Lung Ng, and Fei Li

Abstract

Despite advancements in treatment options, the overall cure and survival rates for non–small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (Npm1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support NPM1 as a therapeutic vulnerability in NSCLC.Significance:Epigenome-wide CRISPR knockout screens identify NPM1 as a novel metabolic vulnerability and demonstrate that targeting NPM1 is a new therapeutic opportunity for patients with NSCLC.

Published
2023

35. Table S5 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai

Abstract

Pathway enrichment of differentially expressed genes (DEG) between mouse LSCC and LADC.

Published
2023

36. Table S1 from Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

Author

Kwok-Kin Wong, Jun Qi, Richard Possemato, George Miller, John T. Poirier, Christina Almonte, Kristen Labbe, Yuanwang Pan, Shuai Li, Val Pyon, Angeliki Karatza, Mousheng Xu, Alireza Khodadadi-Jamayran, Hon-Cheong So, Kai Zhao, Jiehui Deng, Ting Chen, Zhaoyuan Fang, Wei Wang, Michela Ranieri, Qingyuan Huang, Hua Zhang, Paula Zouitine, Kate E.R. Hollinshead, Catríona M. Dowling, Vladislav O. Sviderskiy, Hai Hu, Troy A. Luster, Wai-Lung Ng, and Fei Li

Abstract

Reads count for CRISPR screens

Published
2023

37. Table S1 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai

Abstract

Cell lines models

Published
2023

38. Table S3 from Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

Author

Kwok-Kin Wong, Jun Qi, Richard Possemato, George Miller, John T. Poirier, Christina Almonte, Kristen Labbe, Yuanwang Pan, Shuai Li, Val Pyon, Angeliki Karatza, Mousheng Xu, Alireza Khodadadi-Jamayran, Hon-Cheong So, Kai Zhao, Jiehui Deng, Ting Chen, Zhaoyuan Fang, Wei Wang, Michela Ranieri, Qingyuan Huang, Hua Zhang, Paula Zouitine, Kate E.R. Hollinshead, Catríona M. Dowling, Vladislav O. Sviderskiy, Hai Hu, Troy A. Luster, Wai-Lung Ng, and Fei Li

Abstract

Enriched gene sets in KP cells with or without Npm1 knockdown

Published
2023

39. Supplementary Data from Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

Author

Kwok-Kin Wong, Jun Qi, Richard Possemato, George Miller, John T. Poirier, Christina Almonte, Kristen Labbe, Yuanwang Pan, Shuai Li, Val Pyon, Angeliki Karatza, Mousheng Xu, Alireza Khodadadi-Jamayran, Hon-Cheong So, Kai Zhao, Jiehui Deng, Ting Chen, Zhaoyuan Fang, Wei Wang, Michela Ranieri, Qingyuan Huang, Hua Zhang, Paula Zouitine, Kate E.R. Hollinshead, Catríona M. Dowling, Vladislav O. Sviderskiy, Hai Hu, Troy A. Luster, Wai-Lung Ng, and Fei Li

Abstract

12 supplementary figures

Published
2023

40. Supplementary Figures S1-9 from Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Kwok-Kin Wong, Adam J. Bass, Cassandra Thakurdin, Ming-Sound Tsao, Christine Ng, Lynette M. Sholl, Joshua D. Campbell, Jiehui Deng, Patrick H. Lizotte, Heather Silver, Roderick T. Bronson, Jie Bin Liu, Yuanwang Pan, Val Pyon, Catríona M. Dowling, Eleni Papadopoulos, Ting Chen, Zhong Wu, Jin Zhou, Hua Zhang, and Josephine Hai

Abstract

Figures S1-9

Published
2023

41. Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Author

Hua Zhang, Haiquan Chen, Sittinon Tang, Shougen Cao, Yuanwang Pan, Victor M. Rivera, Shuai Li, Fei Li, Kwan Ho Tang, Hai Hu, Chengwei Peng, Francois Gonzalvez, Hailin Ding, Jiehui Deng, Johara Chouitar, Han Han, Sylvie Vincent, Theresa E. Baker, Michael Fitzgerald, Val Pyon, Ting Chen, Zhendong Gao, Rachael L. Brake, Eleni Papadopoulos, David H. Peng, Jiansheng Wu, Cassandra Thakurdin, Kwok-Kin Wong, and Shengwu Liu

Subjects
Cancer Research, medicine.drug_class, Afatinib, T cell, Poziotinib, Biology, medicine.disease, Tyrosine-kinase inhibitor, Exon, medicine.anatomical_structure, Oncology, Neratinib, medicine, Cancer research, Adenocarcinoma, skin and connective tissue diseases, Lung cancer, medicine.drug
Abstract

No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Published
2021

42. Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

Author

Jun Qi, Michela Ranieri, Wai-Lung Ng, John T. Poirier, Alireza Khodadadi-Jamayran, Fei Li, Qingyuan Huang, Vladislav O. Sviderskiy, Hon-Cheong So, Shuai Li, Kate E.R. Hollinshead, Paula Zouitine, Kwok-Kin Wong, Mousheng Xu, Troy A. Luster, Kai Zhao, Richard Possemato, Wei Wang, Yuanwang Pan, Hai Hu, Kristen E. Labbe, Val Pyon, George Miller, Angeliki Karatza, Zhaoyuan Fang, Ting Chen, Jiehui Deng, Catríona M. Dowling, Christina Almonte, and Hua Zhang

Subjects
0301 basic medicine, Cancer Research, NPM1, education.field_of_study, business.industry, Cell, Population, medicine.disease, respiratory tract diseases, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, Tumor progression, 030220 oncology & carcinogenesis, Cancer cell, medicine, Cancer research, CRISPR, Epigenetics, Lung cancer, education, business
Abstract

Despite advancements in treatment options, the overall cure and survival rates for non–small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (Npm1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support NPM1 as a therapeutic vulnerability in NSCLC. Significance: Epigenome-wide CRISPR knockout screens identify NPM1 as a novel metabolic vulnerability and demonstrate that targeting NPM1 is a new therapeutic opportunity for patients with NSCLC.

Published
2020

43. ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer

Author

Aristotelis Tsirigos, Subhadip Mukhopadhyay, Ting Chen, Mark R. Philips, Jiehui Deng, Hailin Ding, Val Pyon, Ian M. Ahearn, Fei Li, Mirna Bulatović, Antonio Marzio, Justin F. Gainor, Shuai Li, Cassandra Thakurdin, Heather Silver, Peter S. Hammerman, David H. Peng, Eli Rothenberg, John V. Heymach, Michele Pagano, Vajira K. Weerasekara, Yuanwang Pan, Hai Hu, Nathanael S. Gray, Charles M. Perou, Aatish Thennavan, Thales Papagiannakopoulos, Han Han, Baishan Jiang, John T. Poirier, Eleni Papadopoulos, Igor Dolgalev, Kwok-Kin Wong, Gordon J. Freeman, Charles M. Rudin, Nabeel Bardeesy, Eric S. Wang, and Jie Li

Subjects
Cancer Research, Antigen Presentation, Lung Neoplasms, biology, Antigen processing, business.industry, medicine.medical_treatment, Antigen presentation, Autophagy, Intracellular Signaling Peptides and Proteins, Cancer, Immunotherapy, medicine.disease, Article, Immune system, Oncology, Carcinoma, Non-Small-Cell Lung, medicine, biology.protein, Cancer research, Autophagy-Related Protein-1 Homolog, Humans, Antibody, Lung cancer, business
Abstract

Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity. Wong and colleagues show that LKB1-deficient lung tumors are sensitive to autophagy inhibition, which can restore impaired antigen presentation and antitumor immune responses, and propose dual targeting of ULK1 and PD-1 for these tumors.

Published
2021

44. Targeting

Author

Han, Han, Shuai, Li, Ting, Chen, Michael, Fitzgerald, Shengwu, Liu, Chengwei, Peng, Kwan Ho, Tang, Shougen, Cao, Johara, Chouitar, Jiansheng, Wu, David, Peng, Jiehui, Deng, Zhendong, Gao, Theresa E, Baker, Fei, Li, Hua, Zhang, Yuanwang, Pan, Hailin, Ding, Hai, Hu, Val, Pyon, Cassandra, Thakurdin, Eleni, Papadopoulos, Sittinon, Tang, Francois, Gonzalvez, Haiquan, Chen, Victor M, Rivera, Rachael, Brake, Sylvie, Vincent, and Kwok-Kin, Wong

Subjects
Lung Neoplasms, Receptor, ErbB-2, Adenocarcinoma of Lung, Apoptosis, Exons, Mice, SCID, Ado-Trastuzumab Emtansine, Xenograft Model Antitumor Assays, Article, Gene Expression Regulation, Neoplastic, Mice, INDEL Mutation, Mice, Inbred NOD, Antibodies, Bispecific, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, Animals, Humans, Female, skin and connective tissue diseases, Cell Proliferation
Abstract

No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of pre-clinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutant cell lines, the IC(50) of mobocertinib was higher than poziotinib and comparable or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC(50) / WT EGFR IC(50) ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20(YVMA) allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20(G776>VC) lung tumors exhibited a sustained complete response to mobocertinib, while HER2 exon 20(YVMA) tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1) synergized with mobocertinib in HER2 exon 20(YVMA) tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4(+) T cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20(YVMA) insertion-mutant lung adenocarcinoma patients.

Published
2021

45. Epigenetic CRISPR Screens Identify

Author

Fei, Li, Wai-Lung, Ng, Troy A, Luster, Hai, Hu, Vladislav O, Sviderskiy, Catríona M, Dowling, Kate E R, Hollinshead, Paula, Zouitine, Hua, Zhang, Qingyuan, Huang, Michela, Ranieri, Wei, Wang, Zhaoyuan, Fang, Ting, Chen, Jiehui, Deng, Kai, Zhao, Hon-Cheong, So, Alireza, Khodadadi-Jamayran, Mousheng, Xu, Angeliki, Karatza, Val, Pyon, Shuai, Li, Yuanwang, Pan, Kristen, Labbe, Christina, Almonte, John T, Poirier, George, Miller, Richard, Possemato, Jun, Qi, and Kwok-Kin, Wong

Subjects
Lung Neoplasms, Nuclear Proteins, Article, respiratory tract diseases, Epigenesis, Genetic, Mice, Genetic Techniques, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Animals, Heterografts, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, Nucleophosmin
Abstract

Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (Npm1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support NPM1 as a therapeutic vulnerability in NSCLC.

Published
2019

46. MA11.02 Targeting HER2 Exon 20–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor, Mobocertinib

Author

Hao Chen, Zhendong Gao, Hailin Ding, Jiansheng Wu, Yuanwang Pan, Michael Fitzgerald, Sittinon Tang, Kwan Ho Tang, Cassandra Thakurdin, Sylvie Vincent, Rachael L. Brake, Kwok K. Wong, Ting Chen, S. Cao, Val Pyon, C. Peng, Jiehui Deng, Victor M. Rivera, Theresa E. Baker, Fei Li, Hai Hu, Francois Gonzalvez, David H. Peng, Simin Liu, Shihua Li, Eleni Papadopoulos, Johara Chouitar, Han Han, and Hua Zhang

Subjects
Pulmonary and Respiratory Medicine, Lung, business.industry, medicine.drug_class, Mutant, medicine.disease, Tyrosine-kinase inhibitor, Exon, medicine.anatomical_structure, Oncology, medicine, Cancer research, Adenocarcinoma, business
Published
2021

47. Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy

Author

Lynette M. Sholl, Ting Chen, Josephine Hai, Zhong Wu, Patrick H. Lizotte, Cassandra Thakurdin, Jiehui Deng, Christine Ng, Yuanwang Pan, Joshua D. Campbell, Adam J. Bass, Catríona M. Dowling, Jin Zhou, Val Pyon, Roderick T. Bronson, Eleni Papadopoulos, Heather Silver, Jie Bin Liu, Kwok-Kin Wong, Ming-Sound Tsao, and Hua Zhang

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, medicine.medical_treatment, Antigen presentation, Cell, Gene Expression, Mice, Transgenic, Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, SOX2, Genome editing, Cell Line, Tumor, medicine, Biomarkers, Tumor, Cytotoxic T cell, Animals, Humans, Lung, Gene Editing, Immunotherapy, Combined Modality Therapy, Immunohistochemistry, Xenograft Model Antitumor Assays, Immune checkpoint, Organoids, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Genetically Engineered Mouse, Cancer research, Carcinoma, Squamous Cell, Genetic Engineering, Biomarkers
Abstract

Purpose: Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed. Experimental Design: We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines. Results: We show that multiplex gene editing of mouse lung organoids using the CRISPR–Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell–mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti–PD-1 therapy. Conclusions: We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage–inducing therapies in the treatment of LSCC.

Published
2019

48. CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer

Author

Max M. Quinn, Alan L. Leggett, Jack Donaghue, Tinghu Zhang, Annan Yang, Xuzhu Zhang, Ruben Dries, Eric S. Wang, Catríona M. Dowling, Belen Sundberg, William G. Kaelin, Nicholas Kwiatkowski, Richard Bonneau, Matthew G. Oser, Fei Li, Zhixiang He, Vladislav O. Sviderskiy, Kwok-Kin Wong, Gordon J. Freeman, Kandarp Jani, Guo-Cheng Yuan, Kate D. Sutherland, Dayanne M. Castro, Eleni Papadopoulos, Nathanael S. Gray, Heather Silver, Andrew J. Aguirre, Brian Diskin, Mirna Bulatović, Cassandra Thakurdin, Michela Ranieri, Jiehui Deng, Eli Rothenberg, Alexandra R. Rabin, Ting Chen, Ariena Kersbergen, Yandong Yin, Qingyuan Huang, George Miller, Vamsidhar Velcheti, Camilla L. Christensen, Christina Almonte, Val Pyon, Yuanwang Pan, Kristen E. Labbe, Shuai Li, Hua Zhang, Peter S. Hammerman, and Han Han

Subjects
CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Genome instability, Cancer Research, Lung Neoplasms, medicine.medical_treatment, T cell, Programmed Cell Death 1 Receptor, Antineoplastic Agents, CD8-Positive T-Lymphocytes, Chemokine CXCL9, Genomic Instability, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cyclin-dependent kinase, PD-L1, medicine, Animals, Humans, Pyrroles, Inflammation, Micronucleus Tests, biology, Tumor Necrosis Factor-alpha, Immunotherapy, Cell cycle, Small Cell Lung Carcinoma, Cyclin-Dependent Kinases, 030104 developmental biology, medicine.anatomical_structure, Oncology, Immune System, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Pyrazoles, Female, Cyclin-Dependent Kinase-Activating Kinase, DNA Damage, Signal Transduction
Abstract

Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.

Published
2020

49. Abstract 3223: Overcome LKB1 mutated cancer resistance to anti-PD1 treatment

Author

Aristotelis Tsirigos, Fei Li, Val Pyon, Ting Chen, Chelsea Wei Ting Lee, Yuanwang Pan, Charles M. Perou, Aatish Thennavan, Jiehui Deng, Igor Dolgalev, Kwok-Kin Wong, Matthew Harris, Heather Silver, and Eli Rothenberg

Subjects
Cancer Research, business.industry, Tumor-infiltrating lymphocytes, T cell, Cancer, medicine.disease, medicine.disease_cause, medicine.anatomical_structure, Immune system, Oncology, Tumor progression, Cancer cell, Cancer research, medicine, KRAS, Lung cancer, business
Abstract

KRAS/STK11 (LKB1) mutant lung cancers are a subtype of cancer that respond poorly in the clinic to immunotherapies with shorter progression-free survival and overall survival comparing with other KRAS mutant lung cancer patients. Interestingly, this group of patients have high tumor mutational burden (TMB) comparable with other KRAS mutant lung cancers, which usually is an indicator for better response to anti-PD1 treatment. By using genetically engineered mouse model (GEMMs), we found that LKB1 loss of function can cause high level of nonsynonymous mutations, as a consequence of both replication dependent and independent DNA repair machinery dysfunctions. This LKB1 mutant dependent increased mutational load might further synergize with smoking mutagen exposures. When LKB1 function is defective, the neoantigens are not properly presented to T cells, which is required for proper T cell activation and effector T cells expansion. This will lead to insensitivity to anti-PD1 antibodies in high TMB tumors and tolerance to neoantigens produced by cancer cells. We further demonstrated that using a small molecule drug that impacts on the LKB1 downstream effector pathway, we can reverse this process through activating innate immunity in tumors, which will restore the antigen presentation functions. Combinational treatment of this small molecule with anti-PD1 can reverse the tumor progression in vivo, through releasing the suppressive tumor infiltrating lymphocytes (TILs) in LKB1 mutant lung cancers. Our study not only helps to further our understanding of the mechanism that contributes to immune evasion in high TMB tumors, but also provides a potential solution for LKB1 mutant cancers to overcome resistance to anti-PD1 treatment in the clinic. Citation Format: Jiehui Deng, Aatish Thennavan, Yuanwang Pan, Igor Dolgalev, Ting Chen, Heather Silver, Matthew Harris, Val Pyon, Fei Li, Chelsea Lee, Aristotelis Tsirigos, Eli Rothenberg, Charles M. Perou, Kwok-Kin Wong. Overcome LKB1 mutated cancer resistance to anti-PD1 treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3223.

Published
2019

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