Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer.

Epidermal growth factor receptor (EGFR) is over-expressed in about 50% of Triple negative breast cancers (TNBCs), but EGFR inhibitors have not been effective in treating TNBC patients. Increasing evidence supports that autophagy was related to drug resistance at present. However, the role and the mechanism of autophagy to the treatment of TNBC remain unknown. In the current study, we investigated the effect of autophagy inhibitor to gefitinib (Ge) in TNBC cells in vitro and in nude mice vivo. Our study demonstrated that inhibition of autophagy by 3-Methyladenine or bafilomycin A1 improved Ge's sensitivity to MDA-MB-231 and MDA-MB-468 cells, as evidence from stronger inhibition of cell vitality and colony formation, higher level of G0/G1 arrest and DNA damage, and these effects were verified in nude mice vivo. Our data showed that the mitochondrial-dependent apoptosis pathway was activated in favor of promoting apoptosis in the therapy of Ge combined autophagy inhibitor, as the elevation of BAX/Bcl-2, Cytochrome C, and CASP3. These results demonstrated that targeting autophagy should be considered as an effective therapeutic strategy to enhance the sensitivity of EGFR inhibitors on TNBC.