Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer

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 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.

Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas

“…Our data suggest that T cells are not necessary to halt tumor progression upon Kras G12V elimination, but they contribute to achieving CRs. Similar results were reported in a recent study using an immunocompetent model of pancreatic ductal adenocarcinoma (PDAC) treated with the KRAS G12D inhibitor MRTX1133 ( 11 ). Notwithstanding the improved therapeutic efficacy of forthcoming KRAS inhibitors, their combination with checkpoint inhibitors or with selective inhibitors of upstream (SOS1, SHP2, RTKs) and downstream (MAPK pathway) effectors is likely to improve the efficacy of anti-KRAS therapies in the clinic.…”

“…Other KRAS G12C inhibitors, such as JDQ443, characterized by a novel binding mode, have been described as well as new compounds that inhibit KRAS noncovalently and independently of its GDP/guanosine triphosphate (GTP) state ( 8 , 9 ). Finally, a novel inhibitor, MRTX1133, selective for the KRAS G12D mutation and capable of blocking the KRAS oncoprotein in its “on” state, has been described ( 10 , 11 ).…”

Oncogenic KrasG12Dspecific 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

“…We show that MRTX1133 has significant impact on the growth of early stage tumors with tumor stasis observed in all human xenograft models, as also shown in other recent studies (Kemp et al, 2023). We demonstrate that MRTX1133 inhibits proliferation of PDAC cells and suppresses pERK, and such activity has a dominant impact on inducing tumor inhibition; While other studies have suggested that CD8 + T cells are not required for suppression of tumor growth in subcutaneous and orthotopic PDAC tumors, they involve short term experiments using mice with small tumor burden (Kemp et al, 2023). In this setting, it is likely tumor stasis due to suspended proliferation can appear effective but if all the cancer cells are not eliminated, tumor reemergence is possible.…”

With a little help from my T friends: T cells increase efficacy of KRAS (G12D) inhibitors

“… 3 Although not yet ready for clinical use, this drug can provide valuable information in the pre-clinical setting, especially when applied to in vivo models that closely mimic the human disease. This is what the Stanger lab did in their recent work in Cancer Discovery , 1 where they studied the efficacy of MRTX1133 in immunocompetent murine models of pancreatic cancer. Kemp and colleagues use both implantable and spontaneous mouse models expressing the KRAS-G12D oncogene (the so-called KPC mice), in the presence of an intact immune system.…”

“… Mutation-selective KRAS inhibitors are revolutionizing the treatment of RAS-mutant tumors but cannot achieve durable effects alone. Kemp and colleagues 1 recently showed how the KRAS-G12D-specific inhibitor MRTX1133, while impairing cancer proliferation, stimulates T cell infiltration, which is crucial for sustained disease control. …”