A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer

Abstract

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent in vitro and in vivo antitumor efficacy against KRASG12D-mutant cancer cells, especially in PDAC, leading to its recent initiation of a phase I/II clinical trial. Here, we provide a summary of the recent advancements related to the use of MRTX1133 for treating KRASG12D-mutant PDAC, focusing on its efficacy and underlying mechanistic actions. In addition, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bringing about a paradigm shift in its management.

Figure 1.. Genetic mutations in PDAC initiation and development.

(A) Multi-stage initiation and progression model of PDAC. As cells acquire mutations in genes like KRAS, CDKN2A, TP53 and SMAD4, along with other less commonly mutated genes, the lesion progresses from low grade pancreatic intraepithelial neoplasia (PanIN1) through PanIN2 and high grade PanIN3, and ultimately to become invasive adenocarcinoma. In PDAC, intrinsic signals such as the KRAS^G12D mutation and extrinsic signals like EGFR activation contribute to an immune-suppressive and desmoplastic microenvironment through reciprocal interactions between tumor cells and diverse stroma cells. Examples of these stroma cells include cancer-associated fibroblasts (blue), cancer-associated macrophages (pink), myeloid-derived suppressor cells (green), among others. (B) Prevalence of KRAS mutant variants in human pancreatic cancer.

Figure 2.. KRAS protein functioning switch and key downstream signaling pathways.

In normal conditions, when cells receive extracellular signals through transmembrane receptors, RAS-selective guanine nucleotide exchange factors (GEFs) and GTP-activating proteins (GAPs) regulate GDP- and GTP-bound KRAS cycling. In cancer cells, KRAS mutations disrupt its intrinsic GTPase activity, causing it to be locked in the GTP-bound and active form. This leads to the constitutive activation of downstream signaling pathways, such as the RAF/MEK/ERK pathway and the PI3K/AKT/mTOR pathway, promoting cancer cell proliferation and survival. The small molecular inhibitor AMG 510 specifically targets the KRAS^G12C mutation, while MRTX1133 specifically targets the KRAS^G12D mutation. However, cancer cells can potentially develop resistance to KRAS inhibitors through multiple mechanisms that may include compensation or feedback activation of the ErbB/wild-type KRAS and YAP signaling, acquisition of additional KRAS/NRAS/HRAS mutations, and etc.

Figure 3.. Chemical structure of MRTX1133 and the orally effective prodrug 9.

The amine moiety highlighted in green is believed to be a major contributor to its poor absorption in the gastrointestinal tract. Prodrug 9, which incorporates specific modifications to the amino group, demonstrated enhanced oral bioavailability compared to MRTX1133. Refer to ref. for details.