Therapeutic targeting of RAS-mediated resistance in oncogene-driven lung cancer.
Researchers identified how lung cancers resist targeted therapy and showed in models that combining existing drugs overcomes this resistance, supporting upcoming clinical trials.
Using complementary tissue and liquid biopsy in 590 patients across multiple oncogene-driven lung cancer types, this multicenter study demonstrates RAS alterations as a clinically significant (~10%) off-target resistance mechanism to EGFR, ALK, MET, ROS1, and RET targeted therapies, with KRAS G12D being the predominant subtype at osimertinib resistance. Patient-derived models established at progression confirm that combining osimertinib with novel selective (zoldonrasib) or pan-RAS (daraxonrasib) inhibitors produces marked in vitro and in vivo synergy, providing direct preclinical rationale for clinical trials.
What the study was
- Study design
- Retrospective multicohort study with patient-derived model preclinical validation
- Population
- 590 patients with oncogene-driven lung cancer (EGFR-mutant, ALK+, MET-amplified, ROS1+, RET-rearranged) progressing on targeted therapies
- Sample size
- 590
- Category
- Genomics/Precision Medicine
- Maturity
- Validated
- Journal
- Annals of oncology
Why it surfaced
Largest systematic characterization of RAS-mediated resistance across oncogene-driven lung cancers (n=590, 5 driver subtypes), combined with patient-derived model validation of novel RAS inhibitor combinations; published in Annals of Oncology, directly informing next-line clinical trial design in a large lung cancer population. Design quality conservative (1) as primarily retrospective cohort + preclinical.
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