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.