Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significant benefits to patients with non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations; however, acquired resistance limits their long-term efficacy. Therefore, it remains an urgent requirement to discover the underlying mechanisms and investigate novel therapeutic strategies for overcoming the resistance to EGFR TKIs. The present study aimed to determine the mechanism underlying the resistance of NSCLC cells to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, the osimertinib-resistant NSCLC cell sub-line HCC827/OR was established in the present study. It was found that the expression levels of Bcl-2 and Bcl-xL were significantly upregulated in resistant cells compared with sensitive cells. Furthermore, the suppression of Bcl-2 and Bcl-xL through small interfering RNA-mediated gene knockdown or using a small molecule specific inhibitor ABT-263 re-sensitized HCC827/OR cells to osimertinib treatment. Moreover, the combined treatment of HCC827/OR cells with ABT-263 and osimertinib enhanced the rate of cell apoptosis through the mitochondrial apoptotic pathway. Finally, ABT-263 was able to overcome the resistance of osimertinib in xenograft tumor models. In conclusion, these findings may provide an improved concept for the development of a novel combined therapeutic strategy for the treatment of NSCLC resistance to EGFR TKIs.