USP9X mediates an acute adaptive response to MAPK suppression in pancreatic cancer but creates multiple actionable therapeutic vulnerabilities - read online free

Sep 24, 2026

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Pancreatic ductal adenocarcinomas with KRAS mutations often resist MEK inhibitor treatment. The study shows that MEK inhibition rapidly induces Mcl-1 by promoting an association between the deubiquitinase USP9X and Mcl-1, stabilizing Mcl-1 and suppressing apoptosis. Blocking Mcl-1 directly or inhibiting its transcription via CDK inhibitors prevents this adaptive response and enhances tumor regression when combined with MEK inhibitors. USP9X is identified as an additional therapeutic target.

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Article USP9X mediates an acute adaptive response to MAPK suppression in pancreatic cancer but creates multiple actionable therapeutic vulnerabilities Authors Naiara Perurena, Rebecca Lock, Rachel A. Davis, ..., Owen J. Sansom, Andrew J. Aguirre, Karen Cichowski Correspondence [kcichowski@rics.bwh.harvard.edu](kcichowski@rics.bwh.harvard.edu) In brief Perurena et al. show that PDACs are resistant to MEK inhibitors because they trigger the formation of USP9X:Mcl-1 complexes, thereby acutely stabilizing Mcl-1 and inhibiting apoptosis. Resistance can be overcome by targeting Mcl-1 with direct inhibitors or by suppressing Mcl-1 transcription with CDK inhibitors, revealing new therapeutic strategies for PDAC. d Mcl-1 upregulation is an adaptive response to MEK inhibition in PDAC d MEK inhibitors acutely stabilize Mcl-1 protein by inducing Mcl-1:USP9X complexes d Combined MEK/Mcl-1 inhibitors trigger dramatic tumor regression in PDACs d MEK/CDK inhibition represents a second promising therapeutic strategy for PDACs Perurena et al., 2023, Cell Reports Medicine 4, 101007 April 18, 2023 ª 2023 [https://doi.org/10.1016/j.xcrm.2023.101007](https://doi.org/10.1016/j.xcrm.2023.101007) ll ll OPEN ACCESS Article USP9X mediates an acute adaptive response to MAPK suppression in pancreatic cancer but creates multiple actionable therapeutic vulnerabilities Naiara Perurena,1,2,3,4 Rebecca Lock,1,2,3 Rachel A. Davis,1,2 Srivatsan Raghavan,2,3,5,6 Natalie F. Pilla,1,2 Raymond Ng,5,6 Patrick Loi,1,2,3 Caroline J. Guild,1,2 Abigail L. Miller,1,2,3 Ewa Sicinska,7 James M. Cleary,3,5 Douglas A. Rubinson,3,5 Brian M. Wolpin,3,5 Nathanael S. Gray,8 Sandro Santagata,3,4,9 William C. Hahn,2,3,5,6 Jennifer P. Morton,10,11 Owen J. Sansom,10,11 Andrew J. Aguirre,2,3,5,6 and Karen Cichowski1,2,3,4,12,* 1Genetics Division, Brigham and Women’s Hospital, Boston, MA 02115, USA 2Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA 3Harvard Medical School, Boston, MA 02115, USA 4Ludwig Center at Harvard, Boston, MA 02115, USA 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 6Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 7Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA 02115, USA 8Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA 9Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA 10Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK 11Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G11 1QH, UK 12Lead contact *Correspondence: [kcichowski@rics.bwh.harvard.edu](kcichowski@rics.bwh.harvard.edu)[ ](kcichowski@rics.bwh.harvard.edu)[https://doi.org/10.1016/j.xcrm.2023.101007](https://doi.org/10.1016/j.xcrm.2023.101007) SUMMARY 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 R

FAQs

Why are many pancreatic ductal adenocarcinomas resistant to MEK inhibitors?

They trigger a rapid adaptive response that stabilizes the anti-apoptotic protein Mcl-1, protecting cells from apoptosis under MEK suppression.

What mechanism does USP9X play in this resistance?

MEK inhibitors induce USP9X to associate with Mcl-1, leading to acute Mcl-1 stabilization through reduced degradation.

How can resistance be overcome according to the study?

Use Mcl-1 direct inhibitors or CDK inhibitors that suppress Mcl-1 transcription, in combination with MEK inhibitors, to induce tumor regression.

Sep 24, 2026

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