Exploiting Canonical TGFß Signaling in Cancer Treatment.

ABSTRACT

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