Journal
CELL REPORTS MEDICINE
Volume 4, Issue 4, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2023.101007
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Pancreatic ductal adenocarcinomas (PDACs) with KRAS mutations are often resistant to MEK inhibitors. This study reveals that MEK inhibitors upregulate Mcl-1 through its association with USP9X, leading to cell survival. Mcl-1 inhibitors and CDK inhibitors can prevent this response and induce tumor regression when combined with MEK inhibitors. USP9X is identified as a potential therapeutic target.
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 thera-peutic 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.
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