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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.