Integrin β3 Promotes Resistance to EGFR-TKI in Non-Small-Cell Lung Cancer by Upregulating AXL through the YAP Pathway

Integrin beta 3 plays a key role in the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), but the development of integrin beta 3 inhibitors has been stalled due to the failure of phase III clinical trials for cancer treatment. Therefore, it is imperative to find a potentially effective solution to the problem of acquired resistance to EGFR-TKI for patients with integrin-beta 3 positive non-small-cell lung cancer (NSCLC) by exploring novel downstream targets and action mechanisms of integrin beta 3. In the present study, we observed that the expression of integrin beta 3 and AXL was significantly upregulated in erlotinib-resistant NSCLC cell lines, which was further confirmed clinically in tumor specimens from patients with NSCLC who developed acquired resistance to erlotinib. Through ectopic expression or knockdown, we found that AXL expression was positively regulated by integrin beta 3. In addition, integrin beta 3 promoted erlotinib resistance in NSCLC cells by upregulating AXL expression. Furthermore, the YAP pathway, rather than pathways associated with ERK or AKT, was involved in the regulation of AXL by integrin beta 3. To investigate the clinical significance of this finding, the current well-known AXL inhibitor R428 was tested, demonstrating that R428 significantly inhibited resistance to erlotinib, colony formation, epithelial-mesenchymal transformation and cell migration induced by integrin beta 3. In conclusion, integrin beta 3 could promote resistance to EGFR-TKI in NSCLC by upregulating the expression of AXL through the YAP pathway. Patients with advanced NSCLC, who are positive for integrin beta 3, might benefit from a combination of AXL inhibitors and EGFR-TKI therapy.

Automated summary

In this study, it was found that Integrin β3 upregulates the expression of AXL through the YAP pathway, leading to resistance to EGFR-TKI in NSCLC. Combination therapy of AXL inhibitors and EGFR-TKI may benefit advanced NSCLC patients positive for Integrin β3.