Genomic profiling of uterine leiomyosarcomas reveal frequent alterations in Akt/mammalian target of rapamycin (mTOR) pathway genes and other actionable genomic abnormalities linked to targeted therapies

Based on our current understanding of ARID1A function, it is difficult to predict a therapeutic strategy for these tumours. Therefore we adopted an unbiased approach using integrated functional and molecular profiling of ARID1A mutant and wild-type tumour cell models. Methods: We profiled two parallel systems; a panel of ARID1A mutant and wild-type OCCC cell lines models and an isogenic pair of ARID1A proficient and deficient HCT116 cell lines, using high throughput screening with chemical and siRNA libraries. This has been integrated with molecular profiling data generated from exome and RNA sequencing to aid the discovery of novel targets. Results: Using functional screens we have identified critical genetic dependencies and potential therapeutics in a series of clear cell ovarian cancer models. Specifically, we have established that dasatinib is selective for OCCC models with loss of function ARID1A mutations both in vitro and in vivo. Dasatinib is not only selective for ARID1A mutant OCCC models, but experimental induction of ARID1A deficiency drives dasatinib sensitivity in ARID1A wild-type OCCC models as well as in isogenic cell systems (both mouse and human) where ARID1A has been rendered dysfunctional by gene targeting. Conclusions: These results provide a framework for the discovery of therapeutic targets for clear cell ovarian cancer characterised by ARID1A mutations. Using an unbiased drug and siRNA sensitivity screening approach, we have identified dasatinib as a candidate therapeutic approach for OCCC. This Dasatinib/ARID1A synthetic lethal approach can be observed both in in vitro and in vivo and suggests that dasatinib should be assessed in clinical trials in OCCC patients.