ARID1AisaDNAbindingsubunitoftheSWI/SNFcomplexthatismutatedinover50%ofovarianclearcell carcinoma (OCCC) cases, which results in its loss of expression in over 90% of ARID1A-mutated OCCC cases. There is an urgent need for effective treatment approaches for ARID1A-mutated OCCCs since OCCCs are generally refractory to standard agents used to treat ovarian cancer and, when diagnosed in advancedstages,OCCCscarrytheworstprognosisofallovariancancersubtypes.Theoverallgoalofmy application is to develop a novel therapeutic approach for ARID1A-mutated OCCCs by targeting the endoplasmic reticulum (ER) stress response. The ER stress response restores intracellular integrity and promotes tumor cell survival, which has emerged as a viable therapeutic target for developing cancer therapeutics.However,whetherARID1AplaysaroleinregulatingtheERstressresponsehasneverbeen explored.IhavediscoveredthatARID1AmutationdrivesanincreaseintheERstressresponseinOCCCs. Using the TCGA database and ARID1A ChIP-seq analysis, my preliminary data suggests that ARID1A containingSWI/SNFdirectlyrepressesthetranscriptionofXBP1,akeymediatoroftheERstressresponse. Consistently, ARID1A mutation correlates with an increase in the ER stress response. I hypothesize that theSWI/SNFcomplexsuppressesXBP1expressionunderERstressconditionsandpotentiatesthe ERstressresponsetopromotetumorcellsurvival.Ihaveproducedpreliminarydatashowingthatthe inhibitionofXBP1signalingreducesOCCCcellgrowthinanARID1Astatusdependentmanner.Accordingly, IhavedevelopedtwoSpecificAimstotestmyhypothesis.
In Aim1, Iwillinvestigatethemechanisticbasis by which ARID1A mutation promotes the ER stress response in OCCCs. I will also explore whether the inhibition oftheER stress response is selective in ARID1A mutanttumors.
In Aim2, I will determinenovel therapeuticstrategiesforARID1A-mutatedOCCCsbytargetingtheERstressresponseincombinationwith platinum-basedchemotherapythatisknowntoinduceERstress.Tomyknowledge,thisdataisthefirstof itskindlinkingARID1A?stumorsuppressorfunctiontotheERstressresponse.Mydataalsopresentsanovel therapeutic strategy for the inhibition of XBP1 signaling in ARID1A-mutated OCCCs. Since ARID1A is the most frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from thecurrentstudieswillhavebroadimplicationsformanydifferenttypesofcancersaswell.
Ovarian clear cell carcinoma (OCCC) possesses a frequent mutation in an important protein that regulates gene expression called ARID1A. In this study, I aim to understand how the mutation of this protein causes the ER stress response which promotes tumor cell survival. Completion of this project will result in a novel therapeutictargetthatcanenhanceOCCCpatientprognosis.