2. Academic Validation
  3. KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells

KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells

  • Cancer Cell. 2023 Aug 23;S1535-6108(23)00242-8. doi: 10.1016/j.ccell.2023.07.002.
Krishnan K Mahadevan 1,  Kathleen M McAndrews 1,  Valerie S LeBleu 2,  Sujuan Yang 1,  Hengyu Lyu 3,  Bingrui Li 1,  Amari M Sockwell 1,  Michelle L Kirtley 1,  Sami J Morse 1,  Barbara A Moreno Diaz 1,  Michael P Kim 4,  Ningping Feng 3,  Anastasia M Lopez 3,  Paola A Guerrero 5,  Francesca Paradiso 6,  Hikaru Sugimoto 1,  Kent A Arian 1,  Haoqiang Ying 7,  Yasaman Barekatain 1,  Lakshmi Kavitha Sthanam 1,  Patience J Kelly 1,  Anirban Maitra 8,  Timothy P Heffernan 9,  Raghu Kalluri 10
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Feinberg School of Medicine and Kellogg School of Management, Northwestern University, Chicago, IL, USA.
  • 3 TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Break Through Cancer, Cambridge, MA, USA.
  • 6 Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].
  • 9 TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].
  • 10 Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioengineering, Rice University, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: [email protected].
PMID: 37625401 DOI: 10.1016/j.ccell.2023.07.002
Abstract

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in Cancer cells and facilitates CD8+ T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    99.93%, KRAS G12C Inhibitor
    Ras