Grant: Project Grant

ARID1A and ARID1B are two sister genes that produce critical members of a large protein complex, named SWI/SNF, that binds to DNA and regulates the accessibility of DNA, thereby controlling the expression of genetic information stored in DNA during normal development. Mutations that inactivate both ARID1A and ARID1B are recently found in a highly aggressive subset of endometrial cancers. These cancers remain hard to treat because they are resistant to conventional chemotherapies. To translate the finding of ARID1A and ARID1B dual loss, yet not directly targetable, for therapeutic development, we have recently performed unbiased genetic screens and found that endometrial cancer cells with dual loss of both ARID1A and ARID1B rely on the residual activity of SWI/SNF. In this proposed work, we aim to elucidate the mechanism underlying the dependency on the residual SWI/SNF complex in ARID1A and ARID1B-defective endometrial cancer cells; we will also evaluate the potential clinical utility of targeting the residual SWI/SNF complex with selective inhibitors in ARID1A and ARID1B-defective endometrial cancers. We propose that ARID1A and ARID1B dual loss alters the formulation of the residual SWI/SNF complex and change their DNA targeting specificity to promote the expression of a novel set of genes critical for tumor growth. Through performing systematic and complementary biochemical, histopathological and drug testing experiments in a variety of model systems, including cell culture, primary patient tumors and mouse models of cancer, we will not only shed light on the molecular pathogenesis of ARID1A and ARID1B-dual deficient endometrial cancers, but also validate the potential of targeting the residual SWI/SNF complex with available therapeutic agents to treat these aggressive cancers. Our findings will also influence the treatment of ARID1A and ARID1B-dual deficient cancers arising from other organs, such as ovary, gastrointestinal and urological tracts.