Figure 6
Targeting the autophagy pathway to potentiate the efficacy of HER2-targeted drugs in breast cancer.
In HER2 gene-amplified breast carcinoma cells primarily responsive to trastuzumab, pharmacological blockade of HER2 signaling causes not only cell death but also autophagy, which acts as a survival mechanism that can be acquired during development of secondary resistance to trastuzumab (top panel). An enhanced basal autophagy may similarly confer primary (inherent) resistance to HER2-targeted drugs (bottom panel). The observations that anti-HER2 drugs alone induce autophagy44,59,60,61, coupled with the evidence that autophagy plays an active role in resistance to anti-HER2 agents, strongly suggest that additional studies should unambiguously define whether it represents a novel mechanism of resistance to anti-HER2 therapies in vivo. For instance, if trastuzumab-refractory patients have higher basal rates of autophagy than those that response well to trastuzumab-based therapies, the knowledge gained from such studies would enable clinicians to use the genetic status of key autophagy regulators (e.g., ATG1243) to predict therapeutic responses and tailor specific regimens (e.g., the FDA-approved anti-malarial agents chloroquine) to optimize clinical outcomes for HER2 gene-amplified breast cancer patients. Blocking HER2 and autophagy simultaneously might overcome both inherent and acquired resistance and restore sensitivity of HER2 gene-amplified breast cancer cells to HER2-targeted therapies including trastuzumab.
