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Variable efficacy of the non-covalent KRASG12D inhibitor (MRTX-1133) with obesity in murine pancreatic cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月8日

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  • Sujith Sarvesh,
  • Holly Stephens,
  • Pia Muri,
  • Henry Nnaemeka Ogbonna,
  • Jianqing Zhang,
  • Karen Aikhionbare,
  • Dhana Sekar Reddy Bandi,
  • Cherlene Hardy,
  • Ganji Purnachandra Nagaraju,
  • Bassel F. El-Rayes,
  • Lyse A. Norian,
  • Jeremy B. Foote

摘要

Previous studies indicate that Diet-induced-obesity (DIO) promotes pancreatic tumor progression, immunosuppression, and resistance to chemotherapy. Here, we evaluated the impact of DIO on efficacy of KRASG12D-specific inhibitor MRTX1133 in syngeneic mouse PDAC cell lines implanted into lean and DIO mice. MRTX1133 induced regression in the 2838c3 syngeneic murine PDAC model irrespective of body condition. However, DIO promoted recruitment of gMDSC and reductions in cytotoxic T cells within the 2838c3 T-cell inflamed TME, correlating with loss of control of microscopic disease. These findings suggest that DIO reduces the potency of targeted KRASG12D inhibition in T cell-inflamed PDAC.