KRASG12D Inhibition Reprograms the Microenvironment of Early and Advanced Pancreatic Cancer to Promote Fas-Mediated Killing by CD8+ T Cells

Authors

Krishnan K Mahadevan
Kathleen M McAndrews
Valerie S LeBleu
Sujuan Yang
Hengyu Lyu
Bingrui Li
Amari M Sockwell
Michelle L Kirtley
Sami J Morse
Barbara A Moreno Diaz
Michael P Kim
Ningping Feng
Anastasia M Lopez
Paola A Guerrero
Francesca Paradiso
Hikaru Sugimoto
Kent A Arian
Haoqiang Ying
Yasaman Barekatain
Lakshmi Kavitha Sthanam
Patience J Kelly
Anirban Maitra
Timothy P Heffernan
Raghu Kalluri

Publication Date

9-11-2023

Journal

Cancer Cell

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.

Keywords

Humans, CD8-Positive T-Lymphocytes, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment

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Associated Data

PMID: 37625401