# Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors

## TL;DR

This paper reviews how targeting SMAD signaling, which can both suppress and promote tumors, could lead to better cancer therapies.

## Contribution

The paper provides a review of preclinical studies on SMAD-regulating inhibitors in epithelial and mesenchymal tumors.

## Key findings

- TGF-β/SMAD signaling has dual tumor-suppressing and tumor-promoting roles.
- Inhibitors targeting SMAD-regulating proteins show potential in preclinical studies.
- Challenges remain due to the complex and context-dependent nature of SMAD signaling.

## Abstract

SMADs are the canonical intracellular effector proteins of the TGF-β (transforming growth factor-β). SMADs translocate from plasma membrane receptors to the nucleus regulated by many SMAD-interacting proteins through phosphorylation and other post-translational modifications that govern their nucleocytoplasmic shuttling and subsequent transcriptional activity. The signaling pathway of TGF-β/SMAD exhibits both tumor-suppressing and tumor-promoting phenotypes in epithelial-derived solid tumors. Collectively, the pleiotropic nature of TGF-β/SMAD signaling presents significant challenges for the development of effective cancer therapies. Here, we review preclinical studies that evaluate the efficacy of inhibitors targeting major SMAD-regulating and/or -interacting proteins, particularly enzymes that may play important roles in epithelial or mesenchymal compartments within solid tumors.