Exploiting Canonical TGFb Signaling in Cancer Treatment

Abstract

TGFb is a pleiotropic cytokine that plays critical roles to define cancer cell phenotypes, construct the tumor microenvironment, and suppress antitumor immune responses. As such, TGFb 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 TGFb in cancer remains elusive. Here, we review the mechanisms by which TGFb acts to oppose successful cancer therapy, the reported prognostic and predictive value of TGFb biomarkers, and the potential impact of inhibiting TGFb in precision oncology. Paradoxically, the diverse mechanisms by which TGFb impedes therapeutic response are a principal barrier to implementing TGFb inhibitors because it is unclear which TGFb mechanism is functional in which patient. Companion diagnostic tools and specific biomarkers of TGFb targeted biology will be the key to exploiting TGFb biology for patient benefit.