Abstract 4697: The PI3K/mTOR pathway is a potential therapeutic target in cancers with ARID1A mutations

The chromatin remodeling SWI/SNF complex is mutated in 20% of all cancers and ARID1A is the most frequently mutated subunit. However, the tumor suppressive functions of ARID1A are not fully understood and no feasible therapeutic strategies are available for ARID1A-mutant cancers. Recent studies found that loss of ARID1A is associated with increased phosphorylation of AKT. We found that from a study that analyzed data from Project Achilles, a broad shRNA screening project, PIK3CA is the number 2 gene essential for survival of ARID1A-mutant cell lines compared to ARID1A-wildtype cell lines (P = 7.37 × 10-6, FDR < 0.001). Based on these findings, we hypothesized that the PI3K pathway is a potential therapeutic target in ARID1A-mutant cancers. We analyzed the Cancer Genome Atlas (TCGA) datasets and found that mutations in the PI3K pathway co-occur with ARID1A mutations. In addition, the number of co-existing PI3K pathway mutations in the same sample is higher when ARID1A is mutated. We knocked down PIK3CA in ARID1A-wildtype cells (RMG1 and OVCAR3) and ARID1A-mutant cells (OVAS and HCH-1). We found that proliferation was impaired more profoundly in ARID1A-mutant cells. Interestingly, HCH-1 cells are wildtype in PIK3CA, PTEN, PIK3R1 and KRAS, but are still sensitive to PIK3CA depletion. For an unbiased approach, we analyzed the Genomics of Drug Sensitivity in Cancer datasets, which contain drug responses of a large cancer cell line panel to 138 anti-cancer drugs. We compared the drug responses of 49 cell lines harboring inactivating ARID1A-mutations with 266 ARID1A-wildtype cell lines. We found that the presence of inactivating ARID1A mutations is highly associated with sensitivity to mTOR inhibitor AZD8055 (ranked 2nd, P = 2.00 × 10-3) and AKT inhibitor MK2206 (ranked 4th, P = 7.98 × 10-3). This association is still significant for MK2206 when we removed cell lines with PIK3CA, KRAS, PTEN, PIK3R1 and TSC1 alterations (P = 1.32 × 10-2). Finally, we investigated how ARID1A loss can directly increase PI3K/mTOR activity. Using microarray analysis, we found that knockdown of ARID1A up-regulated MYC and MYC target genes, including SLC7A5, an amino-acid transporter required for mTOR activation. Analysis of TCGA datasets showed that MYC amplification and ARID1A mutations are mutual exclusive events, suggesting that overexpression of MYC and loss of ARID1A may converge on the same pathway. In conclusion, we found that ARID1A-mutant cells are highly sensitive to PI3K/mTO