Therapeutic targeting of RAS-mediated resistance in oncogene-driven lung cancer.

RAS alterations mediate resistance in about 10% of oncogene-driven lung cancer patients, with KRAS G12D enriched among cases progressing on osimertinib.

• Why it matters: Even with next-generation targeted therapies, most patients relapse, and off-target resistance mechanisms limit durable control. The study addresses whether RAS alterations contribute to resistance and can be therapeutically targeted.
• What they did: Tissue and liquid biopsies were analyzed across 590 patients with EGFR-mutant disease on osimertinib and ALK/MET/ROS1/RET inhibitor-treated cancers. Two patient-derived models with acquired KRAS mutations at osimertinib progression (G12D and G12R) were used to test osimertinib plus zoldonrasib or daraxonrasib.
• The result: RAS alterations were found in 35 of 312 osimertinib progressors (11.2%), enriched for KRAS G12D (n = 10) and rare for KRAS G12C (n = 1). In the KRAS-mutant models, osimertinib combined with either zoldonrasib or daraxonrasib showed marked synergistic activity in vitro and in vivo.

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