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 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 14d. 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 anti-tumor 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.

<p>Antibody lists</p>

<p>MRTX1133 elicits changes in the tumor stroma and vasculature</p>

<p>Effects of MRTX1133 in KPC/Y and subcutaneous models</p>

<p>Supplementary Figures and Table with legend arranged in a single presentable package</p>

<div>Abstract<p>Mutations in the <i>KRAS</i> oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (<i>KRAS</i>^G12D) being the most common. Here, we tested the efficacy of a small-molecule KRAS^G12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. <i>In vitro</i> studies validated the specificity and potency of MRTX1133. <i>In vivo</i>, 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 <i>KRAS</i>^G12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.</p>Significance:<p>Pharmacologic inhibition of KRAS^G12D 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.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-22-1304" target="_blank">See related commentary by Redding and Grabocka, p. 260</a>.</i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-2-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 247</a></i></p></div>

<p>MRTX1133 exerts in vivo effects early in treatment</p>

<div>Abstract<p>Mutations in the <i>KRAS</i> oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (<i>KRAS</i>^G12D) being the most common. Here, we tested the efficacy of a small-molecule KRAS^G12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. <i>In vitro</i> studies validated the specificity and potency of MRTX1133. <i>In vivo</i>, 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 <i>KRAS</i>^G12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.</p>Significance:<p>Pharmacologic inhibition of KRAS^G12D 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.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-22-1304" target="_blank">See related commentary by Redding and Grabocka, p. 260</a>.</i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-2-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 247</a></i></p></div>