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12 results on '"Patrick P, Zarrinkar"'

1. Figure S1 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Figure 1

Published
2023

2. Data from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Purpose:KRAS-mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy.Experimental Design: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C–activating mutation in vitro and in vivo. We used a second-generation KRAS G12C inhibitor, ARS1620 with improved bioavailability over the first generation. We analyzed KRAS downstream effectors signaling to identify mechanisms underlying differential response. To identify candidate combination strategies, we performed a high-throughput drug screening across 112 drugs in combination with ARS1620. We validated the top hits in vitro and in vivo including patient-derived xenograft models.Results:Response to direct KRAS G12C inhibition was heterogeneous across models. Adaptive resistance mechanisms involving reactivation of MAPK pathway and failure to induce PI3K–AKT pathway inactivation were identified as likely resistance events. We identified several model-specific effective combinations as well as a broad-sensitizing effect of PI3K-AKT–mTOR pathway inhibitors. The G12Ci+PI3Ki combination was effective in vitro and in vivo on models resistant to single-agent ARS1620 including patient-derived xenografts models.Conclusions:Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.

Published
2023

3. Figure S5 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Figure 5

Published
2023

4. Table S1 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Table 1

Published
2023

5. Figure S2 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Figure 2

Published
2023

6. Figure S4 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Figure 4

Published
2023

7. Figure S6 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Figure 6

Published
2023

8. Figure S7 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Figure 7

Published
2023

9. Data S3 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Data 3

Published
2023

10. Data S2 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Data 2

Published
2023

11. Figure S3 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Supplementary Figure 3

Published
2023

12. Supplementary Figures Legends from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Author

Cyril H. Benes, Aaron N. Hata, Yi Liu, Lian-Sheng Li, Matthew R. Janes, Patrick P. Zarrinkar, Ellen Murchie, Giovanna T. Stein, Joseph McClanaghan, Regina K. Egan, Patricia Greninger, Varuna Nangia, Max Greenberg, Maria Gomez-Caraballo, Dana Lee, David T. Myers, Daria Timonina, Samantha Bilton, Chendi Li, Eliane Cortez, Jackson P. Fatherree, and Sandra Misale

Abstract

Legends to supplementary table, data and figures

Published
2023

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