Improved Therapy for Breast Cancer by Inhibiting Autophagy

摘要

Inhibitors of growth factor receptors such as trastuzumab (herceptin) or lapatinib inhibit downstream signaling kinases including mTOR which it is predicted would induce the cells to undergo autophagy. While autophagy may eventually result in cell death, for many days it can recycle intracellular molecules, generating ATP to support cell viability. Hence, it is hypothesized that autophagy will protect tumor cells from trastuzumab and lapatinib. Inhibitors of autophagy would then represent an effective adjuvant to enhance cell killing. It was observed that lapatinib induced autophagy in BT474 breast cancer cells. Autophagy was effectively suppressed using shRNA targeted to ATG12. Lapatinib was shown to completely suppress cell growth, but the cells appeared to survive in a quiescent state with no evidence of cell death. Cells suppressed for autophagy showed no evidence of additional cell death, although evidence was obtained that ATG12 protein levels may have recovered, thereby compromising this experiment. The results obtained are consistent with the original hypothesis that inhibitors of growth factor receptors will induce autophagy. However, we have been unable to confirm that autophagy protects the cells from these drugs which does not support the original hypothesis.