Fig. 2 |. Therapy-induced EMT and potential EMT-suppressing regimens.

Epithelial-mesenchymal transition (EMT) induced by a spectrum of therapeutic agents and modalities has consequences for treatment resistance and/or metastasis across many cancer types. Potential mechanisms through which EMT might contribute to therapeutic resistance include reducing the sensitivity to proapoptotic signals (reviewed in REF.²⁵⁸), acquisition of stemness features^66–69, stimulation of angiogenesis²⁵⁹, upregulating expression of immune checkpoint molecules⁴¹ and increasing immune suppression by altering the balance of infiltrating immune cells^185,237, reducing DNA damage in concert with enhancing DNA repair^260,261, and upregulating expression of export pumps that actively eliminate cytotoxic drugs from cells^262–264. Furthermore, cells undergoing therapy-induced EMT might proliferate at decreased rates and, therefore, have decreased sensitivity to chemotherapeutic agents^34,36,51, and migration of cancer cells to a microenvironment that is poorly accessible to drugs (for example, through the blood-brain barrier) might reduce the impact of therapeutic interventions. For example, in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, continued treatment with HER-targeted therapy (for example, trastuzumab) can trigger EMT²⁶⁵ and relapse can occur in the brain alone despite an ongoing good response elsewhere in the body²⁶⁶. Treatment with existing or novel therapies (for example, eribulin or vinca alkaloids)^211,212 might minimize or revert EMT-associated features and, therefore, reduce the emergence of therapeutic resistance. CRC, colorectal cancer; EMT-TF, EMT-activating transcription factor; HCC, hepatocellular carcinoma; miRNA, microRNA; NSCLC, non-small-cell lung cancer; TGFβ, transforming growth factor-β.