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

Despite the dramatic activity of next generation targeted therapies, most patients with oncogene-driven lung cancers eventually relapse. Novel inhibitors are particularly active against on-target resistance, fostering the emergence of off-target resistance mechanisms. The current clinical development of RAS inhibitors hints at their potential role in overcoming off-target resistance mediated by RAS alterations.

Using tissue and liquid biopsies, we assessed resistance mechanisms to first-line osimertinib in patients with EGFR-mutant lung cancer, and to ALK-, MET-, ROS1-, and RET- inhibitors, for a total of 590 patients. We established two patient-derived models with acquired KRAS mutations obtained at osimertinib progression, enabling in vitro and in vivo functional experiments.

Among 312 patients progressing on first-line osimertinib, we observed a major complementary role of tissue and liquid biopsies in identifying resistance mechanisms. We identified RAS alterations in 35 of 312 patients (11.2%), with an enrichment in KRAS G12D (n = 10) and a paucity of KRAS G12C (n = 1) mutations. In patients with ALK-positive disease (n = 148), RAS alterations were more common at resistance to lorlatinib compared to second-generation inhibitors (14.7% vs 5%, p = 0.0444). Across MET-, ROS1-, and RET-driven lung cancers at progression to targeted agents, RAS alterations were detected in 7-16% of the cases. In the two patient-derived models established at osimertinib resistance with acquired KRAS mutations (G12D and G12R, respectively), we tested the combinatorial effect of osimertinib with either the selective KRAS G12D inhibitor zoldonrasib or the pan-RAS inhibitor daraxonrasib. Both combinations demonstrated marked synergistic activity in vitro and in vivo.

RAS alterations mediate resistance to targeted agents in approximately 10% of oncogene-driven lung cancer. Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.