Protective autophagy promotes the resistance of HER2-positive breast cancer cells to lapatinib.

Lapatinib, a tyrosine kinase inhibitor of HER2/EGFR, can inhibit the proliferation of HER2-positive breast cancer cells. Additionally, the combination of lapatinib and chemotherapy can markedly prolong patient survival time. However, the clinical therapeutic effect of lapatinib is severely limited by drug resistance. We previously found that brief treatment with lapatinib induced both apoptosis and autophagy in HER2-positive breast cancer cells. Additionally, the apoptosis induced by lapatinib was dependent on autophagy. In our current study, however, we used extended treatment of HER2-positive breast cancer cells with lapatinib to confirm the presence of protective autophagy in the previously established lapatinib-resistant cells. Specifically, we found that inhibition of autophagy could reduce the proliferation, DNA synthesis, and colony-forming capacity of resistant cells. Thus, autophagy is a potential novel therapeutic target for reversing lapatinib resistance of HER2-positive breast cancer cells. Our data provide clear, novel evidence of both anti-apoptotic and pro-apoptotic functions of autophagy in breast cancer during lapatinib treatment.