KRAS On-site Mutation Resistance Models

ASP3082, an injectable drug developed by Astellas targeting the KRAS G12D mutation, has received approval from the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China for a new drug clinical trial application (IND). This drug is primarily intended for patients with advanced (unresectable) or metastatic solid malignancies carrying the KRAS G12D mutation and is being developed to treat pre-treated pancreatic cancer, lung cancer, and colorectal cancer.

Currently, ASP3082 has entered Phase I clinical trials (NCT05382559). First-in-human studies began in June 2022 at multiple cancer centers across the United States, bringing renewed hope to the KRAS-targeted therapy field.

KRAS mutations are among the most common genetic alterations in human cancers, comprising a major portion of RAS family mutations and are closely associated with poor prognosis. The RAS protein family (KRAS, NRAS, and HRAS) consists of small GTPases that regulate several key intracellular signaling pathways, including MAPK and PI3K.

Beyond KRAS G12C, KRAS G12D is the most prevalent KRAS mutation type in human cancers, frequently occurring in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). At the recently concluded AACR 2024 Annual Meeting, KRAS G12D emerged as a major research focus, attracting the development of at least 10 drug candidates. Multiple pharmaceutical companies have disclosed the latest progress on their KRAS G12D inhibitors:

Lilly presented preclinical data on LY3962673;
Verastem Oncology in collaboration with GenFleet Therapeutics shared preclinical results of their oral, highly selective KRAS (G12D) inhibitor GFH375/VS-7375 in mouse models of pancreatic and colorectal cancer;
Revolution Medicines released preclinical details of its clinical-stage KRAS (G12D) inhibitor RMC-9805;
TransThera Biosciences unveiled preclinical data on TSN1611, demonstrating strong druggability, in vivo efficacy, and safety for the KRAS G12D target.

However, as with other small molecule inhibitors, the development of KRAS G12D inhibitors faces challenges from acquired target resistance. In studies exploring the resistance mechanisms of MRTX1133, researchers revealed that secondary mutations at the H95 residue could lead to clinical resistance to MRTX1133. In KRAS G12D MEF cells lacking endogenous RAS, additional expression of the HA-KRAS G12D/Y96D double mutant resulted in complete resistance to MRTX1133, with the double mutant remaining in a stable GTP-bound state even in the presence of the drug. Similarly, in the MRTX1133-sensitive human pancreatic cancer cell line Panc10.05 carrying the KRAS G12D mutation, expression of KRAS G12D/H95Q, KRAS G12D/H95L, and KRAS G12D/Y96D double mutants all exhibited complete resistance to MRTX1133. These findings suggest that secondary mutations at H95 and Y96 residues on KRAS are likely key mechanisms of acquired clinical resistance to MRTX1133 and its derivatives.

To support the development of KRAS inhibitor drugs, Kangyuan Bio has constructed a series of KRAS secondary mutation knock-in cell line models for evaluating KRAS-targeted degraders. Compared to the parental cells, these knock-in models exhibit clear resistance to KRAS-G12D and KRAS-G12C inhibitors. Validation data are provided below.

Cell lines list:

Functional Validation

Reference:

Daoyan Wei; Liang Wang; Xiangsheng Zuo; Anirban Maitra; Robert S. Bresalier. A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer. Clin Cancer Res (2024) 30 (4): 655–662.
Miles A. Keats, John J. W. Han, Yeon-Hwa Lee, Chih-Shia Lee, and Ji Luo. A non-conserved histidine residue on KRAS drives paralog selectivity of the KRAS G12D inhibitor MRTX1133. bioRxiv preprint

KRAS On-site Mutation Resistance Models

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Cell lines list:

Functional Validation

Reference: