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

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

doi:10.1016/j.ccell.2023.07.002

KRAS^G12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8⁺ T cells

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 SthanamPatience J. Kelly, Anirban Maitra, Timothy P. Heffernan, Raghu Kalluri

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

The KRAS^G12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRAS^G12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRAS^G12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRAS^G12D-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 KRAS^G12D 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.

Original language	English (US)
Pages (from-to)	1606-1620.e8
Journal	Cancer cell
Volume	41
Issue number	9
DOIs	https://doi.org/10.1016/j.ccell.2023.07.002
State	Published - Sep 11 2023

ASJC Scopus subject areas

Oncology
Cancer Research

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Research Animal Support Facility
Cytogenetics and Cell Authentication Core
Advanced Technology Genomics Core
Flow Cytometry and Cellular Imaging Facility
Small Animal Imaging Facility

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10.1016/j.ccell.2023.07.002

Cite this

Mahadevan, K. K., McAndrews, K. M., LeBleu, V. S., Yang, S., Lyu, H., Li, B., Sockwell, A. M., Kirtley, M. L., Morse, S. J., Moreno Diaz, B. A., Kim, M. P., Feng, N., Lopez, A. M., Guerrero, P. A., Paradiso, F., Sugimoto, H., Arian, K. A., Ying, H., Barekatain, Y., ... Kalluri, R. (2023). KRAS^G12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8⁺ T cells. Cancer cell, 41(9), 1606-1620.e8. https://doi.org/10.1016/j.ccell.2023.07.002

Mahadevan, KK, McAndrews, KM, LeBleu, VS, Yang, S, Lyu, H, Li, B, Sockwell, AM, Kirtley, ML, Morse, SJ, Moreno Diaz, BA, Kim, MP , Feng, N, Lopez, AM, Guerrero, PA, Paradiso, F, Sugimoto, H, Arian, KA, Ying, H, Barekatain, Y, Sthanam, LK, Kelly, PJ, Maitra, A, Heffernan, TP & Kalluri, R 2023, 'KRAS^G12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8⁺ T cells', Cancer cell, vol. 41, no. 9, pp. 1606-1620.e8. https://doi.org/10.1016/j.ccell.2023.07.002

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

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.",

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

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T1 - KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells

AU - Mahadevan, Krishnan K.

AU - McAndrews, Kathleen M.

AU - LeBleu, Valerie S.

AU - Yang, Sujuan

AU - Lyu, Hengyu

AU - Li, Bingrui

AU - Sockwell, Amari M.

AU - Kirtley, Michelle L.

AU - Morse, Sami J.

AU - Moreno Diaz, Barbara A.

AU - Kim, Michael P.

AU - Feng, Ningping

AU - Lopez, Anastasia M.

AU - Guerrero, Paola A.

AU - Paradiso, Francesca

AU - Sugimoto, Hikaru

AU - Arian, Kent A.

AU - Ying, Haoqiang

AU - Barekatain, Yasaman

AU - Sthanam, Lakshmi Kavitha

AU - Kelly, Patience J.

AU - Maitra, Anirban

AU - Heffernan, Timothy P.

AU - Kalluri, Raghu

PY - 2023/9/11

Y1 - 2023/9/11

N2 - 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.

AB - 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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