Synergistic Enhancement of Osimertinib Efficacy in Non-small Cell Lung Cancer Cells Through Epigallocatechin-3-Gallate: Mechanistic Insights Into YAP/TEAD/CTGF Axis Inhibition.

PURPOSE

Combinatorial therapies are essential for treating advanced non-small cell lung cancer (NSCLC), particularly overcoming resistance to third-generation epidermal growth factor receptor (EGFR) like osimertinib (OSI). The Hippo signaling pathway, a critical regulator of cell proliferation, apoptosis, and tumor progression, is often dysregulated in NSCLC and contributes to chemo-resistance. This study investigated the potential of epigallocatechin-3-gallate (EGCG), a green tea polyphenol, to overcome OSI resistance by modulating the Hippo signaling pathway, specifically through inhibition of the YAP-1 (Yes-associated protein)-TEAD (TEA domain transcription factor)-CTGF (connective tissue growth factor) axis.

METHODS

Using stepwise dose escalation, OSI-resistant (OR) clones were developed from EGFR T790M-mutated H460 cells. The anti-proliferative effects of EGCG were assessed, and synergistic interactions between OSI and EGCG were analysed using combination index (CI) values and the median effect concept. Mechanistic studies evaluated the co-treatment's impact on the Hippo signaling pathway, focusing on the inhibition of the YAP/TEAD/CTGF signaling axis.

RESULTS

The OR clones exhibited significantly higher IC values for OSI (25.12-28.48 µM) compared to parental H460 cells (2.74±0.2µM). EGCG treatment reduced cell viability in a concentration-dependent manner, with IC values of 102.54±0.23μM for H460 cells and 225.79-237.36 µM for OR clones. Combination treatment of OSI and EGCG showed strong synergy at a 1:2 molar ratio, with CI values indicating synergism across a range from IC to IC. Mechanistically, co-treatment suppressed the overexpression of the YAP/TEAD/CTGF axis, restoring Hippo pathway activity and reversing OSI resistance.

CONCLUSION

This study provides evidence that EGCG effectively targets the Hippo signaling pathway to overcome OSI resistance in NSCLC. The inclusion of EGCG in combinatorial therapies holds promise as a novel approach to combat therapeutic resistance and improve outcomes for patients with EGFR-mutated NSCLC.