Targeting TGF-β Signaling for Therapeutic Gain

Abstract

Transforming growth factor βs (TGF-βs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-β type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-β ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-β signaling for therapeutic benefit. This review will cover the basics of TGF-β signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-β blockade strategies, and give an update on preclinical and clinical trials for TGF-β blockade in a variety of solid tumor types.

Figure 1.

Context-dependent transforming growth factor β (TGF-β) signaling outputs arise from pathway interactions. Schematic of TGF-β signaling via the canonical Smad pathway (center) or noncanonical signaling pathways (right). Modification of Smad transcriptional output (left) may be by posttranslational modification of Smads, such as by linker phosphorylation by extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) or by the presence or activation status of interacting transcription factors that are regulated by other stress and other growth factor signaling pathways. EGF, Epidermal growth factor; FGF, fibroblast growth factor; TNF, tumor necrosis factor; PI3K, phosphoinositide 3-kinase; JNK, c-Jun amino-terminal kinase.

Figure 2.

Drug targets on the TGF-β signaling pathway. The figure indicates molecular targets during the synthesis, activation, and signaling of TGF-β to which drugs have been raised. Molecular targets and processes are shown in boxes.