title: Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.
abstract: New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1-S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rowan E
authors.initials: RE
authors.lastname: Miller
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brough
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Ilirjana
authors.initials: I
authors.lastname: Bajrami
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Williamson
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: McDade
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Asha
authors.initials: A
authors.lastname: Kigozi
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rumana
authors.initials: R
authors.lastname: Rafiq
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Pemberton
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Natrajan
authors.affiliation: Horizon Discovery, Waterbeach, Cambridge, United Kingdom.
authors.forename: Josephine
authors.initials: J
authors.lastname: Joel
authors.affiliation: Horizon Discovery, Waterbeach, Cambridge, United Kingdom.
authors.forename: Holly
authors.initials: H
authors.lastname: Astley
authors.affiliation: Horizon Discovery, Waterbeach, Cambridge, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Mahoney
authors.affiliation: Horizon Discovery, Waterbeach, Cambridge, United Kingdom.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moore
authors.affiliation: Horizon Discovery, Waterbeach, Cambridge, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Torrance
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors.forename: John D
authors.initials: JD
authors.lastname: Gordan
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors.forename: James T
authors.initials: JT
authors.lastname: Webber
authors.affiliation: Cellular and Molecular Pharmacology University of California, San Francisco, San Francisco, California.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Levin
authors.affiliation: Cellular and Molecular Pharmacology University of California, San Francisco, San Francisco, California. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. Chris.Lord@icr.ac.uk Alan.Ashworth@ucsf.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. Chris.Lord@icr.ac.uk Alan.Ashworth@ucsf.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D000069439:Dasatinib / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D000072020:Synthetic Lethal Mutations; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C112476:ARID1A protein, human; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016283:Proto-Oncogene Proteins p21(ras); D000069439:Dasatinib