Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancer

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Project Summary ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is generally refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in advanced stages, OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this proposal is to develop a novel therapeutic strategy for ARID1A-mutated ovarian cancers by targeting the IRE1a/XBP1 pathway of the endoplasmic reticulum (ER) stress response alone or in combination with an immune checkpoint blockade. We show that the ARID1A inactivation creates a dependence on the IRE1a/XBP1 pathway. We also show that ARID1A inactivation sensitizes ovarian cancer to anti-PD-L1 treatment. The objectives of this application are to investigate the mechanisms underlying the dependence on the IRE1a/XBP1 pathway created by ARID1A inactivation and to investigate novel IRE1a/XBP1 inhibition-based therapeutic strategies for ARID1A-mutated ovarian cancer. Our central hypothesis is that ARID1A-mutated ovarian cancers can be treated and ultimately eradicated by targeting the IRE1a/XBP1 pathway of the ER stress response alone or in combination with immune checkpoint blockade. Two Specific Aims are proposed: Aim 1 is to investigate the mechanism by which ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of the IRE1a/XBP1 pathway; and Aim 2 will target the IRE1a/XBP1 pathway for developing novel therapeutic strategies for ARID1A mutation. The proposed studies are highly innovative because they challenge current research/clinical paradigms and utilize innovative methods to explore new intervention strategies for ARID1A-mutated ovarian cancers. The research proposed is of high impact because it will provide a scientific rationale for developing urgently needed novel therapeutic strategies by targeting the IRE1a/XBP1 pathway of the ER stress response alone or in combination with an immune checkpoint blockade for ARID1A-mutated ovarian cancer, a disease that currently has no effective therapy. Since ARID1A is the most frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.