Abnormally activated OPN/integrin ?V?3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer.

ABSTRACT: Background: Acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance limits the long-term clinical efficacy of tyrosine kinase-targeting drugs. Although most of the mechanisms of acquired EGFR-TKI resistance have been revealed, the mechanism of?~?15% of cases has not yet been elucidated.

Methods: Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Proteome profiler array analysis was performed to find proteins contributing to acquired EGFR-TKI resistance. Secreted OPN was detected by ELISA. Immunohistochemical analysis was conducted to detect expression of integrin ?V in NSCLC tissue. The effect of VS-6063 on apoptosis and proliferation of PC9 gefitinib-resistant cells was detected by fluorescence-activated cell sorting (FACS) and clonogenic assays. A mouse xenograft model was used to assess the effect of VS-6063 on the sensitivity of PC9 gefitinib-resistant cells to gefitinib.

Results: OPN was overexpressed in acquired EGFR-TKI-resistant NSCLCs. Secreted OPN contributed to acquired EGFR-TKI resistance by activating the integrin ?V?3/FAK pathway. Inhibition of FAK signalling increased sensitivity to EGFR-TKIs in PC9 gefitinib-resistant cells both in vitro and in vivo.

Conclusions: OPN contributes to acquired EGFR-TKI resistance by up-regulating expression of integrin ?V?3, which activates the downstream FAK/AKT and ERK signalling pathways to promote cell proliferation in NSCLC.

SUBMITTER: Fu Y 

PROVIDER: S-EPMC7720454 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature