A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment

Abstract

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-β can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-β in cancer cells are blocked, TGF-β signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-β signaling in cancer and summarize the clinical status of TGF-β signaling inhibitors that interfere with TGFβ bioavailability, TGF-βreceptor interaction, or TGF-β receptor kinase function. Moreover, we will discuss targeting of TGF-β signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs.

Keywords: SMAD; TGF-β; cancer therapy; epithelial-to-mesenchymal transition; immune evasion; signaling; tumor microenvironment.

Figure 1

Schematic representation of transforming growth factor (TGF)-β/SMAD signaling. TGF-β is secreted in a latent form, which can be activated via integrin-dependent processes. Activated TGF-β initially engages with co-receptor beta glycan. Thereafter, it is passed on to TβRII that recruits TβRI forming a heteromeric signaling complex. Upon TβR1 phosphorylation and activation by TβRII kinase (phosphorylation indicated with red circle), SMAD2 and SMAD3 are phosphorylated (phosphorylation indicated with red circle) and form complexes with SMAD4. These complexes translocate into nucleus and act as transcription factors to regulate the expression of TGF-β signaling target genes. SMAD7, together with E3 ubiquitin ligase SMURF2, can induce proteasomal/lysosomal degradation of TβRI. This process can be reverted via the action of USP4/15 deubiquitinating enzymes.

Figure 2

Biphasic role of TGF-β/SMAD signaling in cancer progression. TGF-β has a dual function in cancer as a tumor suppressor processes (in blue) and a tumor promoter processes (in red). In normal cells and early stage cancer cells, TGF-β acts as tumor suppressor by inducing cell cycle arrest and apoptosis. However, in late-stage cancer, increased TGF-β signaling can promote cancer progression including epithelial-to-mesenchymal transition (EMT) and angiogenesis. Cellular responses to TGF-β signaling are mediated via SMAD2/3-SMAD4-dependent regulation of specific target genes.

Figure 3

TGF-β signaling mediates EMT. (A) TGF-β is an important player in the activation of EMT, which is characterized by downregulation of epithelial markers and upregulation of mesenchymal markers. TGF-β via either SMAD or non-SMAD signaling can enhance the expression of EMT inducing transcription factors (EMT-TF) such as SNAIL1/2, ZEB1/2, and TWIST. (B) The involvement of miRNA and lncRNAs as important modulators of TGF-β signaling and EMT: miR-10b induces TGF-β-driven EMT by expression of HOXD10. MiR-200 family can negatively regulate ZEB1/2. LncRNA H19 upregulates EMT by interacting with SLUG or EZH2. LncRNA HOTAIR induces EMT by mediating the physical interaction between SNAIL and EZH2.

Figure 4

TGF-β signaling and the tumor microenvironment. TGF-β is expressed by cancer and stromal cells including cancer-associated fibroblasts (CAFs). TGF-β can maintain tumor progression by activating CAFs, stimulating immunosuppression, and promoting angiogenesis.

Figure 5

Targeting TGF-β signaling in cancer. (A) Various TGFβ signaling inhibitors including neutralizing antibodies, ligand traps, and receptor kinase inhibitors are depicted. (B) The structure of TβRI kinase (gray) with its ATP competitive inhibitor: a 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogue (green) (Accession code:1RW8) [82].

Figure 6

Other possible strategies for targeting downstream TGF-β signaling. (A) Targeting TGF-β signaling or its effectors (miRNA, LncRNAs) by antisense oligonucleotides. The stability and specific cell/tissue targeting of the oligonucleotide therapeutic molecules can be enhanced/mediated by nanoparticles. (B) Targeting TGF-β signaling inspired by harnessing the proteasomal machinery to degrade intracellular proteins. Deubiquitinating enzyme (DUB) inhibitor can enhance the degradation (or change the activity) of TGF-β signaling proteins (e.g., TβRs, SMAD3, EMT-TFs) by inhibiting the deubiquitination process. Likewise, proteolysis-targeting chimeras (PROTACs) can induce the proteasomal-mediated degradation of target proteins (SMAD3, EMT-TFs) by recruiting target protein to specific E3 ligases. (C) Interfering protein-protein interaction by cyclic peptides (left) and stapled peptides (right).