Concurrent KRAS and PRMT5 inhibition in MTAP-del/KRAS-mutant pancreatic cancer

The 2021-2022 FDA approval of inhibitors for the KRASG12C mutation for the treatment of lung and colorectal cancer catalyzed the development and clinical evaluation of mechanistically diverse inhibitors targeting nearly all oncogenic RAS mutations. In addition to mutation-selective inhibitors for the most prevalent KRAS mutation, G12D, pan-KRAS and pan-RAS inhibitors are also under clinical evaluation. Currently, more than 65 RAS-targeted inhibitors are being evaluated across over 150 clinical trials. Despite this rapid progress, both primary and acquired resistance severely limit the depth and durability of response to RAS inhibitor monotherapy. Our studies address critical barriers to advancing RAS inhibitor-based therapies in pancreatic ductal adenocarcinoma (PDAC), the most KRAS-addicted cancer type (95%), for which current standards-of-care cytotoxic drug combinations remain largely ineffective. Because G12C mutations are rare in PDAC (>2%), we focus on KRASG12D, the predominant KRAS mutation in PDAC (42%), and on characterization of the clinical candidate KRASG12D on-state inhibitor VS-7375 (GFH375). A central challenge in RAS drug development is the identification of mechanisms of resistance that then inform rational combination strategies that extend clinical benefit. However, to date, co-targeting the “logical suspects” within the RAS signaling network (e.g., SHP2, MEK) has met with limited clinical benefit and increased toxicity. Therefore, we have pursued orthogonal strategies that include targeting the PRMT5 protein arginine methyltransferase, which regulates molecular processes and signaling networks distinct from RAS. We determined that the second-generation, MTA-cooperative PRMT5 inhibitor BMS-986504 preferentially suppressed the growth of MTAP-deleted (22%) but not MTAP wild-type PDAC, and that concurrent PRMT5 inhibition prolonged KRASG12D inhibitor-mediated tumor regression. Mechanistically, we determined that PRMT5 inhibition disrupted RNA splicing of genes essential for PDAC growth, and that PRMT5 and KRAS regulate distinct transcriptomes that then converge on pathways controlling cancer cell proliferation. Our preliminary observations also support non-overlapping mechanisms of resistance, suggesting that this cancer cell mutation-selective combination therapy will provide a strong therapeutic index and more durable clinical responses than monotherapy. Despite these promising findings, how PRMT5 supports PDAC growth remains incompletely understood, given its hundreds of catalytically distinct substrates with diverse molecular and cellular functions. We therefore propose a system-wide characterization of the molecular consequences of PRMT5 inhibition modeled on our recent systemwide analyses of ERK mitogen-activated protein kinase signaling, the key driver of resistance to KRAS inhibitor therapy. Additionally, we will define mechanisms of resistance to PRMT5 inhibition. Together, this information will then guide identification of combination strategies to advance the clinical development of KRASG12D and/or PRMT5- directed therapies for MTAP-deleted/KRASG12D-mutant PDAC.