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Abstract Uveal melanoma (UM) is the most common primary intraocular cancer in adults, with a strong propensity to metastasize, primarily to the liver. Metastatic UM is notoriously unresponsive to existing therapies, rendering it almost uniformly lethal. Virtually all UM tumors have activating mutations in the Gq signaling pathway, predominantly in GNAQ/11, and around half of tumors have additional loss-of-function mutations in the tumor suppressor BAP1. Mutations in the epigenetic modulator BAP1 are the most significant clinical marker of metastatic risk. The limited efficacy of current treatment options necessitates an urgent exploration of novel therapeutic approaches to improve patient prognosis. Thus, we conducted a large epigenetic compound library screen with the currently most well characterized, focused epigenetic library available, which consisted of 960 potent, cell permeable, medically active, epigenetic-directed small molecule modulators (TargetMol, L1200). We screened BAP1-mutant as well as BAP1-wildtype uveal melanoma cell lines and followed up with comprehensive dose-response and synergy tests. Our lead compounds were highly efficient in reducing viability of UM cells. We find that inhibitors with high specificity for class 1 HDAC inhibition are especially cytotoxic to UM cells. Together, our results reveal a possible mechanism of interfering with UM progression and identify lead compounds to be tested in clinical trials. Citation Format: Gulum Yenisehirli, Ashley Zuniga, Sara Rodriguez, Emily V. Adis, Gabriela Quintana, Sebastian Borges, Sofia Lopez, Kassandra Lopez, Steffanie Braun, Claude H. Volmar, J. W. Harbour, Stefan Kurtenbach. Identifying class 1 HDACs as a vulnerability for aggressive uveal melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4581.
Yenisehirli et al. (Fri,) studied this question.
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