Novel FAK inhibitors suppress tumor growth and reverse EGFR-TKI resistance in non-small cell lung cancer

Abstract

Aim: The current study aims to investigate the critical role of the focal adhesion kinase (FAK) oncogenic signaling pathway in mediating drug resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) and evaluate the potential of two novel FAK inhibitors, 10k and 10l, as therapeutic strategies for drug resistant non-small cell lung cancer (NSCLC). Methods: EGFR-TKI resistance in NSCLC cells was developed via stepwise drug selection. Kinases/polymerase chain reaction (PCR) arrays identified key resistance determinants, while reverse transcription quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry evaluated FAK messenger RNA and phosphorylation levels. Antitumor activities were assessed using sulforhodamine-B, clonogenic, wound-healing, and apoptosis assays, spheroids and xenografts. Results: FAK was identified as a key driver of acquired resistance to EGFR-TKIs. High FAK expression predicted poor prognosis in patients treated with EGFR-TKIs. Kinase and PCR profiling confirmed elevated FAK levels as a resistance mechanism. Compounds 10k and 10l reduced phosphorylated FAK and showed strong anti-proliferative, anti-migratory, and pro-apoptotic effects in both EGFR-TKI-sensitive and -resistant cells. Notably, these compounds were shown to resensitize resistant NSCLC cells to EGFR-TKIs, with 10k inhibiting tumor growth and enhancing Osimertinib efficacy in resistant xenografts. Conclusion: These findings not only uncover a pivotal mechanism of EGFR-TKI drug resistance but also highlight innovative, promising therapeutic options for patients with therapy-refractory disease.