Chemotherapy remains the most common treatment for all types of breast cancer. Chemoresistance in tumors is still a major obstacle for treating late-stage breast cancer. In the process of acquiring resistance, tumor cells dynamically evolve to adapt to the challenge of anti-cancer drugs. Besides the upregulation of drug-pumps, signal pathways related to proliferation and survival undergo adaptive evolution. Thus, these drug-resistant cells are more conducive to proliferation, even in stressful conditions. Nevertheless, the detailed mechanism that drives cancer cells to sustain their proliferation ability is unclear. Herein, we reported that the upregulated C-MET signaling acts as a compensatory mechanism that sustains the proliferation of chemoresistant cells in which EGFR family signaling was attenuated. Both C-MET and EGFR family are essential for cell proliferation due to their activation of the STAT3 signaling. Different from other cell models in which C-MET interacts with and phosphorylates EGFR family members, our cell model showed no direct interaction between C-MET and EGFR family members. Therefore, C-MET and EGFR family signaling pathways function independently to sustain the proliferation of resistant cells. Moreover, chemoresistant cells have evolved a novel, STAT3-C-MET feed-forward loop that plays a vital role in sustaining cell proliferation. The activated STAT3 interacts with the MET gene promoter to upregulate its transcription. Most importantly, the combined inhibition of C-MET and EGFR family synergistically inhibits the proliferation of drug-resistant cells in vitro and in xenograft tumor models. This work provides a new strategy for treating drug-resistant breast cancer.Copyright © 2021. Published by Elsevier B.V.
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