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Mol Cancer Ther. 2016 Jul;15(7):1472-84. doi: 10.1158/1535-7163.MCT-15-0554. Epub 2016 Jun 30.

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.

Author information

1
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.
2
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
3
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
4
Horizon Discovery, Waterbeach, Cambridge, United Kingdom.
5
UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
6
Cellular and Molecular Pharmacology University of California, San Francisco, San Francisco, California.
7
Cellular and Molecular Pharmacology University of California, San Francisco, San Francisco, California. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California.
8
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.

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.

PMID:
27364904
DOI:
10.1158/1535-7163.MCT-15-0554
[Indexed for MEDLINE]
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