USP9X mediates an acute adaptive response to MAPK suppression in pancreatic cancer but creates multiple actionable therapeutic vulnerabilities.

Pancreatic ductal adenocarcinomas (PDACs) frequently harbor KRAS mutations. Although MEK inhibitors represent a plausible therapeutic option, most PDACs are innately resistant to these agents. Here, we identify a critical adaptive response that mediates resistance. Specifically, we show that MEK inhibitors upregulate the anti-apoptotic protein Mcl-1 by triggering an association with its deubiquitinase, USP9X, resulting in acute Mcl-1 stabilization and protection from apoptosis. Notably, these findings contrast the canonical positive regulation of Mcl-1 by RAS/ERK. We further show that Mcl-1 inhibitors and cyclin-dependent kinase (CDK) inhibitors, which suppress Mcl-1 transcription, prevent this protective response and induce tumor regression when combined with MEK inhibitors. Finally, we identify USP9X as an additional potential therapeutic target. Together, these studies (1) demonstrate that USP9X regulates a critical mechanism of resistance in PDAC, (2) reveal an unexpected mechanism of Mcl-1 regulation in response to RAS pathway suppression, and (3) provide multiple distinct promising therapeutic strategies for this deadly malignancy.

Informations de copyright

Copyright © 2023. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of interests K.C. is an advisor at Genentech and serves on the scientific advisory board of Erasca, Inc. N.S.G. is a founder, science advisory board (SAB) member, and equity holder in Gatekeeper, Syros, Petra, C4, B2S, Aduro, Inception, Allorion, Jengu, Larkspur (board member), and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Arbella, Deerfield, and Sanofi. A.J.A. has consulted for Oncorus, Inc.; Arrakis Therapeutics; Syros Pharmaceuticals; Boehringer Ingelheim; T-knife Therapeutics; AstraZeneca; and Merck & Co., Inc. and has research funding from Mirati Therapeutics; Syros Pharmaceuticals; Bristol Myers Squibb; Revolution Medicines; Novartis; Deerfield, Inc.; and Novo Ventures that is unrelated to this work. W.C.H. is a consultant for Thermo Fisher, Calyx, Solasta Ventures, MPM, KSQ Therapeutics, Tyra Biosciences, RAPPTA Therapeutics, Function Oncology, Jubilant Therapeutics, and Frontier Medicines. B.M.W. declares research funding from Celgene Inc. and Eli Lilly and Company and consulting for BioLineRx Ltd., Celgene Inc., and GRAIL Inc. O.J.S. receives funding from AstraZeneca, Novartis, Boehringer Ingelheim, Redex, and Cancer Research Technologies. S.S. is a consultant for RareCyte Inc. S.R. holds equity in Amgen.