Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells

Abstract

The metabolic reprogramming of tumor cells plays a critical role in cancer progression, contributing to drug resistance and tumor survival. Tyrosine kinase inhibitors (TKIs) have shown promising clinical results by targeting specific signaling pathways in cancer cell proliferation, survival, and metastasis and are now standard of care for NSCLC with actionable mutations. However, secondary resistance to TKIs remains a significant challenge. Here, we explored the rationale behind combining TKIs with an inhibitor of glucose metabolism (dichloroacetate, DCA), focusing on the synergistic effects from dual inhibition of oncogenic and metabolic reprogramming. We selected three NSCLC cell line models (H1975, H1993, A549) with EGFR/MET/KRAS mutations and determined the optimal DCA dose (500 μM) to reverse the Warburg effect. TKIs in combination with DCA (CI < 1, indicating synergy) altered cell metabolism, by improving oxidative phosphorylation via reduced glucose consumption (~50 %, p < 0.05) and increased ATP (~50 %, p < 0.0001), particularly mitoATP, confirmed by metabolite levels. The combination also reduced cell proliferation (S phase p < 0.001), increased cell death (~40 %, p < 0.0001 less MMP, ~1.6 fold more BIM, 2.5-fold more autophagy) and blocked invasion (~3 fold fewer protrusions). Our findings show DCA potentiates TKIs at lower doses, likely via Warburg effect reversal. These changes in tumor behaviour leads to a higher pro-apoptotic status responsible for an increased tumor response and, in parallel, the lower doses reduced alternative evasion pathways contributing to decrease of tumor invasion and resistance mechanism. This study shed light on a new potential combined therapeutic approach to improve clinical outcomes in targeted cancer therapy scenarios.

Keywords: Cell death; Combined therapy; Oncogene addiction; PDKs.