22 results on '"Annemiek M.C. Gennissen"'
Search Results
2. Supplementary Figure from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition
- Author
-
Katrien Berns, René Bernards, Mark S. Carey, Steven de Jong, Roderick L. Beijersbergen, Cor Lieftink, Christianne A.R. Lok, Gabriel E. DiMattia, Hannah Kim, Madison Bittner, Cheng-Han Lee, Amy Dawson, Joshua Hoenisch, Aleksandra Hamilton, G. Bea A. Wisman, Shang Li, Nelson K.Y. Wong, Annemiek M.C. Gennissen, E. Marielle Hijmans, and Marta Llaurado Fernandez
- Abstract
Supplementary Figure from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition
- Published
- 2023
3. Data from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient–derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient–derived xenograft models.Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928–40. ©2018 AACR.
- Published
- 2023
4. Table S1 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Table 1 | Gene set for kinome sequencing.
- Published
- 2023
5. Supplementary figures and tables legends from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Legends of supplementary figures and tables
- Published
- 2023
6. Table S4 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Table 4 | Clinicopathological characteristics (n=70 patients).
- Published
- 2023
7. Table S2 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Table 2 | Gene set for Haloplex sequencing.
- Published
- 2023
8. Figure S2 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Figure 2 | Significantly mutated genes AKT1, PIK3R1, ERBB3, FBXW7, ATM, CHEK2 and MYO3A. Schematics of the identified novel significantly mutated genes (A) AKT1, (B) PIK3R1, (C) ERBB3, (D) FBXW7, (E) ATM, (F) CHEK2 and (G) MYO3A in OCCC. Mutation marks are shown in black (truncating), red (SIFT and PolyPhen damaging prediction), yellow (SIFT or PolyPhen damaging prediction) or white (SIFT and PolyPhen benign prediction). Mutation effects are indicated with a black spot when paired control was available and written in black (previously described mutation) or red (novel mutations).
- Published
- 2023
9. Table S3 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Table 3 | Binomial testing of kinome sequencing variants.
- Published
- 2023
10. Figure S5_2 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Figure 5 | Clustering (n=106) and survival analysis (n=70) on kinome mutations and CNA. (A) Disease-specific survival of patients (n=70) grouped on ARID1A status, (B) PIK3CA status and (C) ARID1A + PIK3CA status. (D) Consensus clustering, with maximum group count set to 10 and clustering optimization with 1000 repetitions maximum, shows adding of tumors (n=106) as consensus index (horizontally) and empirical cumulative distribution (vertically) for 1-10 clusters. (E) Area under the curve plot of decrease in friction from 1-10 clusters. (F) Heatmap distribution of tumors in 8 clusters. (G) Disease-specific survival of patients (n=70) in 8 clusters, (H) cluster 3 vs. other clusters. (I) Disease-specific survival in advanced stage OCCC patients (FIGO 2C-4), Log rank (Mantel-Cox) was used for statistical analysis. (J) Nonsynonymous mutation distribution in genes involved in the frequently mutated PI3K/AKT/mTOR (blue) and MAPK pathway (yellow), ERBB family of receptor tyrosine kinases (green) and DNA repair pathway (red) as well as ARID1A and PALB2 are shown with OncoPrint. CNA in each mutated gene are added. The 106 OCCC tumors that were both kinome sequenced and SNP arrayed are shown on the horizontal axis grouped on tumor clusters and ordered on total event frequency in the subsequently altered pathways. (K) Oncoprint from advanced stage patients in cluster 3 vs. other clusters, shown on the horizontal axis grouped on tumor clusters and ordered on total event frequency in the subsequent altered pathways, ordered as aforementioned.
- Published
- 2023
11. Figure S3 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Figure 3 | Mutation distribution in OCCC. (A) Nonsynonymous mutation distribution in genes involved in the frequently mutated PI3K/AKT/mTOR (blue) and MAPK pathway (yellow), ERBB family of receptor tyrosine kinases (green) and DNA repair (red) pathway is shown. In this OncoPrint, kinome sequenced OCCC tumors are depicted on the horizontal axis and ordered on mutation frequency in the subsequent altered pathways, represented vertically on the right. ARID1A mutant tumors are displayed at the top. (B) BioVenn diagrams demonstrating overlap in ARID1A mutant tumors and PI3K/AKT/mTOR, MAPK and DNA repair pathway and ERBB family of receptor tyrosine kinases mutant tumors (n=103). On the right, PI3K/AKT/mTOR and MAPK pathway, the ERBB family of receptor tyrosine kinases and DNA repair pathway mutations within only ARID1A wildtype tumors (n=49) and only ARID1A mutant tumors (n=44). All data in A and B is derived from 122 kinome-sequenced OCCC tumors, overlap in BioVenn diagram circles is proportional to group overlap.
- Published
- 2023
12. Figure S5_1 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Figure 5 | Clustering (n=106) and survival analysis (n=70) on kinome mutations and CNA. (A) Disease-specific survival of patients (n=70) grouped on ARID1A status, (B) PIK3CA status and (C) ARID1A + PIK3CA status. (D) Consensus clustering, with maximum group count set to 10 and clustering optimization with 1000 repetitions maximum, shows adding of tumors (n=106) as consensus index (horizontally) and empirical cumulative distribution (vertically) for 1-10 clusters. (E) Area under the curve plot of decrease in friction from 1-10 clusters. (F) Heatmap distribution of tumors in 8 clusters. (G) Disease-specific survival of patients (n=70) in 8 clusters, (H) cluster 3 vs. other clusters. (I) Disease-specific survival in advanced stage OCCC patients (FIGO 2C-4), Log rank (Mantel-Cox) was used for statistical analysis. (J) Nonsynonymous mutation distribution in genes involved in the frequently mutated PI3K/AKT/mTOR (blue) and MAPK pathway (yellow), ERBB family of receptor tyrosine kinases (green) and DNA repair pathway (red) as well as ARID1A and PALB2 are shown with OncoPrint. CNA in each mutated gene are added. The 106 OCCC tumors that were both kinome sequenced and SNP arrayed are shown on the horizontal axis grouped on tumor clusters and ordered on total event frequency in the subsequently altered pathways. (K) Oncoprint from advanced stage patients in cluster 3 vs. other clusters, shown on the horizontal axis grouped on tumor clusters and ordered on total event frequency in the subsequent altered pathways, ordered as aforementioned.
- Published
- 2023
13. Supplementary Methods from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Methods file
- Published
- 2023
14. Figure S7 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Figure 7 | PDX alteration status and p-S6 staining. (A) Nonsynonymous mutation distribution in PDX.155, PDX.180 and PDX.247 in genes involved in the frequently mutated PI3K/AKT/mTOR (blue) and MAPK pathway (yellow), ERBB family of receptor tyrosine kinases (green) and DNA repair pathway (red) as well as ARID1A and PALB2 are shown with OncoPrint. CNA in each mutated gene are added. (B) PDX.155, (C) PDX.180 and (D) PDX.247 representative p-S6 expression after 21 days of vehicle or AZD8055 treatment.
- Published
- 2023
15. Figure S1 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
- Abstract
Supplementary Figure 1 | Kinome sequencing variant filtering. Pipeline for filtering of kinome sequencing variants.
- Published
- 2023
16. ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors
- Author
-
Tesa M. Severson, Gert Jan Meersma, René Bernards, Steven de Jong, Katrien Berns, Bastiaan Evers, G. Bea A. Wisman, Cor Lieftink, Roderick L. Beijersbergen, Joseph J Caumanns, Annemiek M.C. Gennissen, E. Marielle Hijmans, Hiroaki Itamochi, Ate G.J. van der Zee, Targeted Gynaecologic Oncology (TARGON), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
0301 basic medicine ,Cancer Research ,ARID1A ,MYC ,Biology ,Article ,ACTIVATION ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Nuclear protein ,Molecular Biology ,Ovarian Neoplasms ,LANDSCAPE ,Ovary ,COLON-CANCER ,Cancer ,Nuclear Proteins ,Proteins ,medicine.disease ,DNA-Binding Proteins ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Clear cell carcinoma ,Cancer cell ,Mutation ,Cancer research ,Adenocarcinoma ,Female ,Clear cell ,RESISTANCE ,Adenocarcinoma, Clear Cell ,Transcription Factors - Abstract
Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells. Importantly, small molecule inhibitors of the BET (bromodomain and extra terminal domain) family of proteins, to which BRD2 belongs, specifically inhibit proliferation of ARID1A mutated cell lines, both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. BET inhibitors cause a reduction in the expression of multiple SWI/SNF members including ARID1B, providing a potential explanation for the observed lethal interaction with ARID1A loss. Our data indicate that BET inhibition may represent a novel treatment strategy for a subset of ARID1A mutated ovarian clear cell carcinomas.
- Published
- 2018
17. Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
- Author
-
Helga B. Salvesen, Katrien Berns, James D. Brenton, Joseph J Caumanns, Michael J. Birrer, Tushar Tomar, Els Van Nieuwenhuysen, Rudolf S N Fehrmann, Ignace Vergote, Jolanta Kupryjanczyk, Evelien W. Duiker, Roelof J.C. Kluin, René Bernards, An K.L. Reyners, Gert Jan Meersma, Steven de Jong, Beata Spiewankiewicz, Elena Ioana Braicu, G. Bea A. Wisman, Annemiek M.C. Gennissen, E. Marielle Hijmans, Hiroaki Itamochi, Ate G.J. van der Zee, Harry G. Klip, Desiree Weening, Lorenza Mittempergher, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), de Jong, Steven [0000-0001-5831-6997], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,PHARMACOKINETICS ,Cancer Research ,Receptor tyrosine kinase ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Kinome ,Ovarian Neoplasms ,biology ,Nuclear Proteins ,EARLY EVENT ,SOLID TUMORS ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,PARP inhibitor ,PHASE-II ,Heterografts ,Female ,Erlotinib ,Tyrosine kinase ,Signal Transduction ,medicine.drug ,RECURRENT EPITHELIAL OVARIAN ,Class I Phosphatidylinositol 3-Kinases ,Morpholines ,Mechanistic Target of Rapamycin Complex 2 ,Mechanistic Target of Rapamycin Complex 1 ,HUMAN CANCERS ,Article ,Olaparib ,03 medical and health sciences ,ErbB ,Cell Line, Tumor ,medicine ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,MUTATIONS ,ADENOCARCINOMA ,PIK3CA ,ARID1A ,030104 developmental biology ,chemistry ,Mutation ,biology.protein ,Cancer research ,Adenocarcinoma, Clear Cell ,Transcription Factors - Abstract
Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models. Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient–derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055. Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient–derived xenograft models. Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928–40. ©2018 AACR.
- Published
- 2018
18. Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance
- Author
-
Theo A. Knijnenburg, Amir Sonnenblick, René Bernards, Sanne Hindriksen, Fan Zhang, Tjalling Bosse, Lodewyk F. A. Wessels, Christine Desmedt, Wouter Nijkamp, Sibylle Loibl, Sylvain Brohée, Bastiaan Evers, Katrien Berns, Wei Guo, Gordon B. Mills, Annemiek M.C. Gennissen, Christos Sotiriou, Heikki Joensuu, Carsten Denkert, Patrick Neven, Michiel S. van der Heijden, Debora Fumagalli, Roderick L. Beijersbergen, and E. Marielle Hijmans
- Subjects
0301 basic medicine ,Cancer Research ,Receptor, ErbB-2 ,Morpholines ,Breast Neoplasms ,Drug resistance ,Pharmacology ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,MTOR Kinase Inhibitor AZD8055 ,Breast cancer ,Trastuzumab ,Cell Line, Tumor ,Biomarkers, Tumor ,Akt Inhibitor MK2206 ,Journal Article ,Humans ,Medicine ,skin and connective tissue diseases ,Protein Kinase Inhibitors ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Annexin A1 ,Gene knockdown ,business.industry ,TOR Serine-Threonine Kinases ,Nuclear Proteins ,medicine.disease ,3. Good health ,DNA-Binding Proteins ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Cancer research ,Female ,business ,Heterocyclic Compounds, 3-Ring ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Transcription Factors ,medicine.drug - Abstract
Purpose: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. Experimental Design: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FinHer and Responsify were used to validate our findings in patient series. Results: We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab–based therapy. Conclusions: Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression. Clin Cancer Res; 22(21); 5238–48. ©2016 AACR.
- Published
- 2016
19. Abstract 3380: Synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition in ovarian clear cell carcinoma
- Author
-
E. Marielle Hijmans, Gert Jan Meersema, Hiroaki Itamochi, Ate G. van der Zee, Katrien Berns, René Bernards, Steven de Jong, Bea Wisman, Cor Lieftink, Roderick L. Beijersbergen, Joseph J Caumanns, Annemiek M.C. Gennissen, and Bastiaan Evers
- Subjects
Cancer Research ,Mutation ,Wnt signaling pathway ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,Bromodomain ,Small hairpin RNA ,Oncology ,Immunology ,Clear cell carcinoma ,Cancer cell ,medicine ,Cancer research ,Clear cell - Abstract
Introduction: Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Given that ARID1A is inactivated by mutation in over 50% of ovarian clear cell carcinomas, we pursued an ARID1A synthetic lethal screening strategy to identify druggable targets in OCCC. Experimental procedures: We performed synthetic lethal kinome short hairpin (shRNA) screens in a large panel (n=14) of OCCC cell lines having different ARID1A mutation status. Hit validation was performed with isogenic ARID1A ko cell line pairs and in (patient-derived) xenograft mouse models. Summary of the data: We show here that BRD2 inhibition is synthetic lethal with ARID1A mutation in ovarian clear cell cancer cells. Importantly, inhibiting the BET family of proteins, to which BRD2 belongs, with small molecules specifically inhibits proliferation of ARID1A mutated cell lines both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. We demonstrate that ARID1A loss leads to upregulation of the WNT ligand WNT10B, possibly causing a WNT dependency in the ARID1A mutant lines. BET inhibitors cause a reduction in WNT10B expression and WNT target genes such as MYC, JUN and WISP1, providing a potential explanation for the observed synthetic lethal interaction with ARID1A loss. Conclusions: Our study uncovered a new synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition, suggesting a new treatment strategy for ARID1A mutant ovarian clear cell carcinomas. Citation Format: Katrien Berns, Joseph J. Caumanns, E Marielle Hijmans, Annemiek Gennissen, Bastiaan Evers, Bea A. Wisman, Gert Jan Meersema, Cor Lieftink, Roderick L. Beijersbergen, Hiroaki Itamochi, Ate G. van der Zee, Steven de Jong, René Bernards. Synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition in ovarian clear cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3380. doi:10.1158/1538-7445.AM2017-3380
- Published
- 2017
20. A single nucleotide polymorphism in an exon dictates allele dependent differential splicing of episialin mRNA
- Author
-
Annemiek M.C. Gennissen, John Hilkens, H. L. Vos, and M. J. L. Ligtenberg
- Subjects
Transcription, Genetic ,RNA Splicing ,Molecular Sequence Data ,Single-nucleotide polymorphism ,Biology ,Transfection ,Polymerase Chain Reaction ,Exon ,Genetics ,splice ,RNA, Messenger ,Antigens ,Allele ,Gene ,Alleles ,Membrane Glycoproteins ,Polymorphism, Genetic ,Splice site mutation ,Base Sequence ,Mucin-1 ,Nucleic acid sequence ,DNA ,Molecular biology ,RNA splicing ,Nucleic Acid Conformation - Abstract
The episialin gene (MUC1) encodes an epithelial mucin containing a variable number of repeats with a length of twenty amino acids, resulting in many different alleles that can be subdivided into two size classes. The episialin pre-mRNA uses either one of two neighbouring splice acceptor sites for exon 2, which mainly encodes the repeats. Using the genetic polymorphism of the episialin gene to identify different alleles, we show here that the splice site recognition is allele dependent and is based on a single A/G nucleotide difference in exon 2 eight nucleotides downstream of the second splice acceptor site. Transfection experiments confirm that this polymorphic nucleotide regulates the splice site selection. The identity of this nucleotide is in most cases correlated with one of the size classes of the alleles, indicating that mutations altering the number of repeats seldom arise by unequal cross-over between the repeat regions.
- Published
- 1991
21. Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini
- Author
-
John Hilkens, M. J. L. Ligtenberg, H. L. Vos, and Annemiek M.C. Gennissen
- Subjects
Genetics ,chemistry.chemical_classification ,Nucleic acid sequence ,Cell Biology ,Biology ,Biochemistry ,Molecular biology ,Transmembrane protein ,Gene product ,chemistry ,Tandem repeat ,Complementary DNA ,Gene expression ,Glycoprotein ,Molecular Biology ,Gene - Abstract
Episialin is a mucin-type glycoprotein present at the luminal side of most glandular epithelial cells. We have isolated cDNA clones encoding episialin and determined the structure of the gene. The gene encodes a transmembrane protein which consists of, for the greater part, tandem repeats of 20 amino acids. The number of these repeats varies between 40 and 90 among different alleles. The repeats and most of the remainder of the protein are very rich in potential O-linked glycosylation sites. Two different splice variants were found. Interestingly, the proteins encoded by these two variants differ in their signal sequences and in the extreme amino-terminal parts of the mature proteins, suggesting alternative processing of these two species.
- Published
- 1990
22. BS69, a novel adenovirus E1A-associated protein that inhibits E1A transactivation
- Author
-
Ron M. Kerkhoven, Yolande F. M. Ramos, V. Sonntag-Buck, Guus Hateboer, H.G. Stunnenberg, René Bernards, and Annemiek M.C. Gennissen
- Subjects
TBX1 ,Transcriptional Activation ,Transcription, Genetic ,Receptors, Retinoic Acid ,viruses ,Molecular Sequence Data ,Cell Cycle Proteins ,Tretinoin ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Adenoviridae ,Retinoblastoma-like protein 1 ,Transactivation ,Mice ,transactivation ,ElA ,medicine ,Tumor Cells, Cultured ,E2F1 ,Animals ,Humans ,Amino Acid Sequence ,Molecular Biology ,Binding Sites ,General Immunology and Microbiology ,Base Sequence ,General Neuroscience ,TATA-Box Binding Protein ,HEK 293 cells ,Chromosome Mapping ,adenovirus ,Molecular biology ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Retinoic acid receptor ,Adenovirus E1A Proteins ,Carrier Proteins ,Co-Repressor Proteins ,Biologie ,Research Article - Abstract
The adenovirus E1A gene products are nuclear phosphoproteins that can transactivate the other adenovirus early genes as well as several cellular genes, and can transform primary rodent cells in culture. Transformation and transactivation by E1A proteins is most likely to be mediated through binding to several cellular proteins, including the retinoblastoma gene product pRb, the pRb-related p107 and p130, and the TATA box binding protein TBP. We report here the cloning of BS69, a novel protein that specifically interacts with adenovirus 5 E1A. BS69 has no significant homology to known proteins and requires the region that is unique to the large (289R) E1A protein for high affinity binding. BS69 and E1A proteins coimmunoprecipitate in adenovirus-transformed 293 cells, indicating that these proteins also interact in vivo. BS69 specifically inhibits transactivation by the 289R E1A protein, but not by the 243R E1A protein. BS69 also suppressed the E1A-stimulated transcription of the retinoic acid receptor in COS cells, but did not affect the cellular E1A-like activity that is present in embryonic carcinoma cells. Our data indicate that BS69 is a novel and specific suppressor of E1A-activated transcription.
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.