LAUSR

Induced myeloid leukemia cell differentiation protein (MCL1) is a member of the B-cell lymphoma-2 (BCL2) family of apoptosis regulators, which plays a critical role in maintaining cellular homeostasis and promoting cancer cell survival. Increased expression of MCL1 in various cancers has been associated with poor prognosis and resistance to chemotherapeutic and targeted agents. We previously described PRT1419, a novel, potent, selective MCL1 inhibitor that demonstrates anti-tumor efficacy in various preclinical models of solid and hematologic malignancies. PRT1419 is currently under evaluation in Phase I clinical trials in patients with relapsed/refractory hematologic malignancies and advanced solid tumors. To identify novel biomarkers that might predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using publicly available human cancer cell line gene dependency data generated from genome-wide CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with deleterious alterations in PBRM1 (Polybromo 1) displayed a strong dependency on MCL1. PBRM1, also known as BAF180, is a chromatin-targeting subunit of mammalian pBAF (SWI/SNF-B) complexes. PBRM1 is frequently altered in various human cancers but it has a particularly high alteration rate in ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We had previously described alterations in other mammalian SWI/SNF factors as biomarkers of MCL1 inhibitor sensitivity.We observed potent inhibition of tumor growth as well as induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not in PBRM1-WT tumor models. Depletion of PBRM1 via RNAi in PBRM1-WT ccRCC induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming PBRM1-loss cells for caspase-mediated cell death following MCL1 inhibition. Increased MCL1 activity has previously been described as a resistance mechanism to Sunitinib and Everolimus, two approved targeted agents for ccRCC. To investigate if MCL1 inhibition could potentiate the anti-tumor effects of these agents, we evaluated PRT1419 in combination with Sunitinib or Everolimus in PBRM1-loss ccRCC. PRT1419 synergized with both Sunitinib and Everolimus in inhibiting tumor growth in various models. Taken together, these findings suggest PBRM1 loss is associated with sensitivity to MCL1 inhibition in ccRCC and provide rationale for the evaluation of PRT1419 for the treatment for PBRM1-deficient ccRCC Citation Format: Norman Fultang, Brian Vidal, Ashley M. Schwab, Alexander Grego, Diane Heiser, Kris Vaddi, Neha Bhagwat, Peggy Scherle. MCL1 inhibitor PRT1419 demonstrates anti-tumor activity in PBRM1-altered clear cell renal cancer and synergizes with standard of care agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6147.