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

Naiara Perurena¹, Rebecca Lock², Rachel A Davis³

¹Genetics 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.

Cell Reports. Medicine

|April 8, 2023

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.

Insights

Pancreatic cancer (PDAC) resistance to MEK inhibitors is overcome by targeting Mcl-1 stabilization via USP9X. Combining MEK inhibitors with Mcl-1 or CDK inhibitors promotes tumor regression.

Area of Science:

Oncology
Molecular Biology
Cancer Therapeutics

Background:

Pancreatic ductal adenocarcinomas (PDACs) often have KRAS mutations, making them candidates for MEK inhibitor therapy.
However, most PDACs exhibit intrinsic resistance to MEK inhibitors, limiting treatment efficacy.

Purpose of the Study:

To identify the adaptive resistance mechanisms in PDAC treated with MEK inhibitors.
To explore novel therapeutic strategies targeting resistance pathways in PDAC.

Main Methods:

Investigated the role of USP9X in Mcl-1 regulation under MEK inhibition.
Utilized Mcl-1 and cyclin-dependent kinase (CDK) inhibitors in combination with MEK inhibitors.
Assessed tumor regression in preclinical models.

Main Results:

MEK inhibitors induce Mcl-1 upregulation by associating with USP9X, stabilizing Mcl-1 and conferring apoptosis resistance.
This mechanism of Mcl-1 regulation is distinct from canonical RAS/ERK signaling.
Combined therapy with MEK inhibitors and Mcl-1 or CDK inhibitors led to significant tumor regression.

Conclusions:

USP9X plays a critical role in mediating MEK inhibitor resistance in PDAC by stabilizing Mcl-1.
Discovered an unexpected pathway for Mcl-1 regulation in response to RAS pathway inhibition.
Identified USP9X, Mcl-1 inhibitors, and CDK inhibitors as potential therapeutic targets for PDAC treatment.

Read full analysis

Keywords:

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

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