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

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

  • Cell Rep Med. 2023 Mar 31;101007. doi: 10.1016/j.xcrm.2023.101007.
Naiara Perurena 1,  Rebecca Lock 2,  Rachel A Davis 3,  Srivatsan Raghavan 4,  Natalie F Pilla 3,  Raymond Ng 5,  Patrick Loi 2,  Caroline J Guild 3,  Abigail L Miller 2,  Ewa Sicinska 6,  James M Cleary 7,  Douglas A Rubinson 7,  Brian M Wolpin 7,  Nathanael S Gray 8,  Sandro Santagata 9,  William C Hahn 4,  Jennifer P Morton 10,  Owen J Sansom 10,  Andrew J Aguirre 4,  Karen Cichowski 11
Affiliations

Affiliations

  • 1 Genetics Division, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA.
  • 2 Genetics Division, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
  • 3 Genetics Division, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 4 Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 6 Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
  • 7 Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 8 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
  • 9 Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 10 Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G11 1QH, UK.
  • 11 Genetics Division, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 37030295 DOI: 10.1016/j.xcrm.2023.101007
Abstract

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.

Keywords

CDK inhibitors; KRAS; MEK inhibitors; Mcl-1; PDAC; USP9X; therapeutic resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-80013
    99.84%, CDK7 Inhibitor
    CDK