Abstract B012: Defining the role of the BAF complex in primary liver cancers

Abstract

Abstract Incidence and mortality from primary liver cancer are increasing and few effective therapies exist for this deadly disease. Mutations in genes important for chromatin mediated gene regulation commonly occur in both hepatocellular carcinoma and cholangiocarcinoma, the two most common primary liver cancers. Chromatin regulators have been shown to be key modulators of both sensitivity and resistance to therapy response, and therapeutic targeting of chromatin regulators is under development for a wide range of cancers. To uncover chromatin genes that modulate therapy response, we performed epigenome-focused CRISPR screening in the presence of multiple kinases inhibitors (sorafenib, donafenib, cabozantinib). We found that disruption of a specific form of the SWI/SNF chromatin remodeling complex, called BAF, led to therapy resistance. The BAF complex is frequently mutated in both hepatocellular carcinoma and cholangiocarcinoma. Recent studies show that loss of ARID1A and ARID1B, members of the BAF complex, gives rise to liver tumors with morphologies of both hepatocellular carcinoma and cholangiocarcinoma. Critically, because multikinase inhibitors are the most common treatments for advanced hepatocellular carcinoma, our findings suggest patients with BAF mutations would not respond well to these drugs. Using gene expression analysis, genome-wide chromatin localization, and chromatin accessibility assays we are uncovering how altered chromatin state underlies multikinase inhibitor response in BAF mutant tumors. Using high-throughput epigenome focused CRISPR screens we will identify novel modulators of therapy response in liver cancer. Citation Format: Margarita M. Dzama, Deena M. Scoville, Emma D. Bucklan, Jesse R. Raab. Defining the role of the BAF complex in primary liver cancers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B012.