Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer

Oncogene-driven non-small cell lung cancer (NSCLC) is typically treated with targeted therapies to inhibit oncogene downstream signaling pathways and reduce tumor survival. The most common subtypes, EGFR and KRAS mutations, are amenable to these therapies; however, resistance often develops, leading to oncogene-independent metastases. This study explores non-oncogene addiction (NOA) as a novel strategy, targeting essential genes like ATR, which is involved in DNA damage response, and pyruvate dehydrogenase kinases (PDKs), which play a role in energy metabolism. Experiments were conducted using sensitive PC9 and the corresponding osimertinib-resistant cells (PC9/OR), EGFR mutant H1975 and KRAS mutant A549 cells treated with TKIs alongside ATR and DCA inhibitors. Results indicated that combining these approaches could enhance efficacy compared to TKIs alone, suggesting a tailored strategy based on tumor subtype. This research underscores the potential of new therapeutic targets to improve treatment outcomes in NSCLC patients compared to traditional TKI therapies.