Oncogenic Kras^G12Dspecific 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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRASG12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the KrasG12D mutant protein. Here we explore the impact of KrasG12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8+T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8+ T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.

KRAS inhibition activates an actionable CD24 ‘don’t eat me’ signal in pancreas cancer

“…Together, these data indicate that AMG 510 treatment engenders an anti-tumor immune profile, reminiscent of the changes in immune populations in KRAS G12D -driven tumors treated with MRTX1133 (17,44). However, the lack of obvious KRAS inhibition-induced tumor regression in the K C PC model, in contrast to KRAS G12D -driven models, implicates that cancer cells can sustain viability in a relatively 'hot' anti-tumor immune microenvironment.…”

“…3A-B). Recent studies in preclinical models demonstrated that the reprogramming of immune microenvironment, in particular the activation of cytotoxic T cells, is critical for the regression of Kras G12D -driven tumors following MRTX1133 treatment (17,44).…”

Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation

“…To this date published data regarding MRTX1133 showed efficacy against only KRAS G12D and effect on T cells. (30, 34–39)…”

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer

“…Similar findings have been noted with KRAS G12C (18, 35) and KRAS G12D -specific inhibitors (36), which demonstrated either that T cells contribute to the efficacy of targeted mutation-specific KRAS inhibitors or are critical for their long-term control of regrowth from metastatic disease (36). Furthermore, the presence of T cells predicted the response to PD-1 immune checkpoint blockade in preclinical models of NSCLC and PDA (35, 48, 49).…”

“…This data suggests that these models reflect different levels of activation of T cells most notably in 2838c3 model system, which has considerably more putative neoantigens than 7160c2 and increased proportion of CD103 + DCs (34). Diversity within KPC tumor clones is attributed in part to epigenetic patterns of gene expression, such as CXCL-1, which in turn influence the composition and function of immune cells in the TME, has been noted and can also impact growth responses to immune checkpoint blockade (34, 48, 49). Although these differences are more pronounced between models and those with evidence of increased T cell infiltration and function, it is likely that myeloid and T cell responses will vary among preclinical tumor models due to variations in tumor epigenetics that impact the local immune microenvironment (35, 36).…”