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

Background: Oncogene-driven NSCLC are usually treated with targeted therapies using tyrosine kinase inhibitors (TKIs) to inhibit oncogene downstream signaling pathways thus affecting tumor survival and proliferation. EGFR and KRAS mutant NSCLC are the most represented subtypes and they are treated in clinical practice with oncogene-targeting drugs in first and second line, respectively. Unfortunately, the development of oncogene-independent resistant clones limits TKIs efficacy. Here, we used non-oncogene addiction (NOA) as an innovative therapeutic strategy to target other essential proteins that support changes in tumor phenotype. Specifically, we tested for the first time a combination of ATR, involved in DNA damage response, and pyruvate dehydrogenase kinases (PDKs), involved in energy metabolism, inhibitors. Methods: Sensitive PC9 and the corresponding EGFR-TKI-resistant PC9/OR, EGFR mutant H1975 and KRAS mutant A549 NSCLC cells were treated with TKIs (osimertinib and selumetinib, respectively). In parallel, cells were exposed to two combination regimens: one using the TKI with ATR inhibitor and the other one combining the two selected NOA inhibitors (ATR inhibitor, M4344 and PDK inhibitor, DCA). Results: The effect of these two combined approaches, compared to TKI alone, produced similar results in terms of cell proliferation, cell death and migration. Thus, depending on tumor biology, the selection among these proposed therapeutic strategies will be different to maximize tumor response. Conclusions: The major translational relevance of this study is to exploit new targets for innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within oncogenes pathway, to overcome resistance to TKI therapies in oncogene-addicted NSCLC patients.