‘Knowing the Type of KRAS Mutation Is Critical’ in Managing KRAS-Mutant NSCLC

By: Joshua D. Madera, MD
Posted: Tuesday, January 14, 2025

The increased resistance to KRAS inhibitors has motivated clinical researchers to investigate the downstream signaling cascade of KRAS-mutant isoforms in the hopes of identifying novel therapeutic strategies for patients with non–small cell lung cancer (NSCLC), according to a study published in Molecular Cancer. Management strategies should be tailored to individual RAS mutants and their respective downstream signaling pathways, suggested Angeliki Malliri, PhD, of The University of Manchester, United Kingdom, and colleagues.

“Knowing the type of KRAS mutation is critical, especially now with the new wave of KRAS isoform–specific inhibitors emerging, which require combinatorial treatments to maximize therapeutic efficacy and decrease resistance,” explained the investigators.

Genetically engineered mouse models were used to compare the tumor development of KRAS G12C and KRAS G12D. In addition, RNA sequencing was used to profile isogenic models of initiation and adaptation to determine mutant subtype–specific dependencies. Therapeutic vulnerabilities of KRAS-mutant NSCLC were assessed via pharmacologic inhibition, and overall survival outcomes were measured.

The in vivo study findings revealed that KRAS G12D had an increased potency, leading to decreased overall survival and more rapid development of lung tumors, compared with KRAS G12C. Findings from the isogenic models suggest this enhanced potency may be attributable to increased signaling in the PI3K-AKT-mTOR cascade. Evaluation of the oncogenicity and downstream pathway activation of KRAS G12C and KRAS G12D showed no significant differences at later stages of tumorigenesis. However, specific differences in pathway dependence were revealed. KRAS G12D depended on the PI3K-AKT-mTOR pathway, and KRAS G12C depended on the MAPK pathway.

Disclosure: The study authors reported no conflicts of interest.

Molecular Cancer

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