2. Academic Validation
  3. Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer

Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer

  • Cancer Res. 2025 Jul 22. doi: 10.1158/0008-5472.CAN-25-1507.
Kristina Drizyte-Miller 1,  Lars D Engstrom 2,  Jeffrey A Klomp 3,  Clint A Stalnecker 4,  Addison G Stamey 1,  Khalilah E Taylor 4,  Mallory K Roach 3,  Ryan Robb 5,  Laura M Waters 2,  Andrew Calinisan 2,  Seamus Degan 1,  Wen-Hsuan Chang 1,  Xousaen M Helu 2,  David Nguyen 2,  Elisa Baldelli 6,  Mariaelena Pierobon 6,  Emanuel F Petricoin 7,  David M Briere 2,  Jill Hallin 8,  James G Christensen 2,  Kirsten L Bryant 4,  Adrienne D Cox 5,  Peter Olson 2,  Channing J Der 5
Affiliations

Affiliations

  • 1 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
  • 2 Mirati Therapeutics (United States), San Diego, CA, United States.
  • 3 University of North Carolina at Chapel Hill, United States.
  • 4 University of North Carolina at Chapel Hill, Chapel Hill, United States.
  • 5 University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
  • 6 George Mason University, Manassass, VA, United States.
  • 7 George Mason University, Manassas, VA, United States.
  • 8 Iambic Therapeutics, San Diego, CA, United States.
PMID: 40694535 DOI: 10.1158/0008-5472.CAN-25-1507
Abstract

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in MTAP-deleted (MTAP-del) cancers. The MTA-cooperative PRMT5 Inhibitor BMS-986504 exhibited potent and selective anti-tumor activity in MTAP-del preclinical models and demonstrated activity in MTAP-del patients without the toxicity associated with previous PRMT5 inhibitors. Here, we focused on pancreatic ductal adenocarcinoma (PDAC), ~22% of which are MTAP-del, and demonstrated that BMS-986504 suppressed PRMT5 function and cell growth in MTAP-del cells and xenograft models. CRISPR/Cas9 loss-of-function screens implicated co-targeting KRAS as a combination strategy. Concurrent inhibition of PRMT5 and KRASG12C/D enhanced and prolonged suppression of PDAC growth. RNA-sequencing analysis revealed that PRMT5 inhibition disrupted RNA splicing of genes essential for PDAC growth. While PRMT5 and KRAS regulated distinct transcriptomes, they converged on pathways governing Cancer cell growth and expression of PDAC-essential genes. These findings provide rationale for combined inhibition of PRMT5 and KRAS in MTAP-deleted/KRAS-mutant PDAC.

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