Increased expression of miR‐641 contributes to erlotinib resistance in non‐small‐cell lung cancer cells by targeting NF1

Epidermal growth receptor (EGFR)‐targeted tyrosine kinase inhibitors (TKIs) have emerged as first‐line drugs for advanced non‐small‐cell lung cancer (NSCLC) patients with EFGR mutations. However, most patients with NSCLC show acquired resistance to EGFR‐TKIs, and low expression of NF1 is a mechanism of EGFR‐TKI resistance in lung cancer. However, the mechanism by which NF1 is downregulated in EGFR‐TKI‐resistant NSCLC is unclear. Here, we found the increased expression of miR‐641 in NSCLC cells and human NSCLC samples with resistance to TKI compared to those with sensitive to TKI. In addition, our in vitro experiments show that overexpression of miR‐641 induces TKI resistance in NSCLC cells. Furthermore, we identified that miR‐641 activates ERK signaling by direct targeting of neurofibromatosis 1 (NF1) in NSCLC cells. Our data show that overexpression of NF1 or silencing of ERK can block miR‐641‐induced resistance of NSCLC cells to erlotinib treatment. Importantly, our animal experiments show that combination of miR‐641 inhibition and erlotinib treatment can significantly inhibit erlotinib‐resistant NSCLC growth, inhibit proliferation and induce apoptosis compared to single‐drug treatment. Our findings suggest that increased expression of miR‐641 significantly contributes to erlotinib resistance development in NSCLC cells through activating ERK signaling by targeting NF1 and that inhibition of miR‐641 may reverse acquired resistance of NSCLC cells to erlotinib treatment.