A Multitude of Mechanisms Contributes to Transforming Growth Factor β Signaling-Mediated Cancer Drug Resistance

Therapy resistance is a major obstacle to cancer treatment and transforming growth factor-beta (TGF-β) signaling has emerged as a major player across many cancer types and therapeutic regimens. Solid tumors overexpress TGF-β ligands, and canonical and non-canonical TGF-β signaling pathways drive molecular changes in most cell types within the tumor, hijacking therapeutic responses. Cancer therapies per se further stimulate TGF-β release potentiating this problem. Molecular mechanisms of TGF-β action include upregulation of drug efflux pumps, enhanced DNA Damage Repair, elaboration of stiffened extracellular matrix, and decreased neoantigen presentation. TGF-β induced epithelial to mesenchymal transition causes tumor heterogeneity and acquisition of stem-like states. TGF--β also activates pro-survival pathways, such as epidermal growth factor receptor, B-cell lymphoma-2 expression, and AKT-mTOR signaling. In the tumor microenvironment, TGF-β induces extracellular matrix production, contractility, and secretion of immunosuppressive cytokines by cancer associated fibroblasts that contribute to drug resistance. TGF-β also blunts cytotoxic T and NK cell activities, and stimulates recruitment and differentiation of immunosuppressive cells, in-cluding T-regulatory cells, M2 macrophages and myeloid-derived suppressor cells. The importance of TGF-β sig-naling in development of drug resistance cannot be understated and should be further explored mechanistically to identify novel molecular approaches and drug sequencing strategies to prevent drug-resistance.