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

Background: Non-small cell lung cancer (NSCLC) driven by oncogenes is typically treated with tyrosine kinase inhibitors (TKIs), which target signaling pathways essential for tumor survival and proliferation. Among these, EGFR- and KRAS-mutant NSCLC represent the most common subtypes and are treated with targeted therapies as first- and second-line options, respectively. However, the efficacy of TKIs is frequently compromised by the emergence of oncogene-independent resistant clones. To address this limitation, we explored non-oncogene addiction (NOA) as a novel therapeutic approach, targeting essential proteins that sustain tumor phenotype adaptations. Specifically, we evaluated, for the first time, a combination of inhibitors targeting ATR, a key regulator of the DNA damage response, and pyruvate dehydrogenase kinases (PDKs), which are involved in energy metabolism.
Methods: We utilized sensitive EGFR-mutant PC9 cells and their EGFR-TKI-resistant counterpart PC9/OR, along with EGFR-mutant H1975 and KRAS-mutant A549 NSCLC cell lines. Treatments included TKIs (osimertinib for EGFR-mutant and selumetinib for KRAS-mutant cells) and two combination regimens: one pairing TKIs with an ATR inhibitor and another combining two NOA inhibitors (ATR inhibitor M4344 and PDK inhibitor DCA).
Results: Both combination regimens demonstrated comparable effects to TKIs alone in reducing cell proliferation, inducing cell death, and impairing migration. These findings suggest that the choice of therapeutic strategy should be tailored to the tumor’s biological characteristics to maximize response.
Conclusions: This study highlights the translational potential of leveraging NOA-targeting drugs as a novel therapeutic strategy to overcome TKI resistance. By targeting essential non-oncogene pathways, these approaches may offer a promising alternative to combinations focusing solely on oncogene-driven pathways.