Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer
TLDR
Redding et al. as discussed by the authors tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system.Abstract:
Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247. read more
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Oncogenic KrasG12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8+ T cells dependent manner
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,Hikaru Sugimoto,Kent A. Arian,Haoqiang Ying,Yasaman Barekatain,Patience J. Kelly,Anirban Maitra,Timothy P. Heffernan,Raghu Kalluri +21 more
TL;DR: In this article , the impact of KrasG12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment was explored, and it was shown that inhibition of mutant Kras in PDAC with human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8+T cell mediated death.
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