Exploiting Canonical TGFb Signaling in Cancer Treatment

TGF beta is a pleiotropic cytokine that plays critical roles to define cancer cell phenotypes, construct the tumor microenvironment, and suppress antitumor immune responses. As such, TGF beta is a lynchpin for integrating cancer cell intrinsic pathways and communication among host cells in the tumor and beyond that together affect responses to genotoxic, targeted, and immune therapy. Despite decades of preclinical and clinical studies, evidence of clinical benefit from targeting TGF beta in cancer remains elusive. Here, we review the mechanisms by which TGF beta acts to oppose successful cancer therapy, the reported prognostic and predictive value of TGF beta biomarkers, and the potential impact of inhibiting TGF beta in precision oncology. Paradoxically, the diverse mechanisms by which TGF beta impedes therapeutic response are a principal barrier to implementing TGF beta inhibitors because it is unclear which TGF beta mechanism is functional in which patient. Companion diagnostic tools and specific biomarkers of TGF beta targeted biology will be the key to exploiting TGF beta biology for patient benefit.