TGF-β Signaling and Resistance to Cancer Therapy

Abstract

The transforming growth factor β (TGF-β) pathway, which is well studied for its ability to inhibit cell proliferation in early stages of tumorigenesis while promoting epithelial-mesenchymal transition and invasion in advanced cancer, is considered to act as a double-edged sword in cancer. Multiple inhibitors have been developed to target TGF-β signaling, but results from clinical trials were inconsistent, suggesting that the functions of TGF-β in human cancers are not yet fully explored. Multiple drug resistance is a major challenge in cancer therapy; emerging evidence indicates that TGF-β signaling may be a key factor in cancer resistance to chemotherapy, targeted therapy and immunotherapy. Finally, combining anti-TGF-β therapy with other cancer therapy is an attractive venue to be explored for the treatment of therapy-resistant cancer.

Keywords: TGF-β; TGF-β pathway; chemotherapy resistance; immunotherapy resistance; targeted therapy resistance.

FIGURE 1

TGF-β signaling pathway TGF-β transduces signaling through SMAD or non-SMAD signaling pathways. Actived TGF-β binds to TGF-β ligand, Once TGF-β binds to TβRII, TβRI is recruited, phosphorylated and activated to phosphorylate the downstream mediators-SMAD2 and SMAD3; then SMAD4 binds to activated SMAD2 and SMAD3 to form heterotrimeric transcriptional complexes that translocate and relay this signaling into the nucleus to further regulate transcription. This is called canonical TGF-β/SMAD signaling pathway (right). The non-SMAD-dependent activation of the TGF-β pathway involves signaling via RHO GTPases, P38, JNK, ERK or MEKK, and PI3K-AKT (left). Abbreviations: P, phosphorylation; TβR, transforming growth factor (TGF)-β receptor; ROCK, RHO-associated coiled-coil containing protein kinase; LIMK, LIM kinase; TRAF, TNF receptor-associated factor; TAK1, TGF-β-activated kinase-1. JNK, c-Jun N-terminal kinase; SHC, SRC homology 2 domain-containing transforming protein; GRB2, growth factor receptor-bound protein 2; SOS, son of sevenless; MEK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-4,5-bisphosphate; mTOR, mechanistic target of rapamycin.

FIGURE 2

TGF-β signaling and resistance to targeted therapy Cancers with activating BRAF-mutations or EGFR-mutations as well as HER2-positive cancer are often treated with small molecular inhibitors against these molecular targets. For example, BRAF^V600E is often targeted by BRAFi such as vemurafenib, MEK by MEKi such as tramelinib, and HER2 by trastuzumab, Upon kinase inhibitor treatment, receptor tyrosine kinase (RTK) signaling is turned off. In cells that activate TGF-β-induced drug resistance, TGF-β signaling functions by increasing the expression of EGFR, PDGFR, ERK, AKT/STAT to activate alternative survival pathways and suppress apoptosis, protecting tumor cells from targeted therapy.

FIGURE 3

TGF-β signaling and resistance to chemotherapy; Multiple miRNAs are implicated in TGF-β-induced chemotherapy resistance in various cancer types by targeting components of the TGF-β pathway (SMAD2, SMAD3, SMAD4). Anti-microtubule drugs promote Bcl-2 protein ubiquitination, which could be inhibited by TGF-β signaling to induce taxane resistance in malignancies. Hyperactivation of TGF-β signaling pathway induces resistance to DNA damaging agents and anti-metabolites through the activation of alternative survival pathways or anti-apoptotic signaling such as PI3K/AKT and ERK pathways, as well as elevated expression of ABC multi-drug transporters to facilitate cancer cell survival and drug efflux, respectively.

FIGURE 4

TGF-β signaling and resistance to immunotherapy; As an immunosuppression cytokine, TGF-β is secreted by both tumor and stromal cells. TGF-β signaling pathway directly inhibits T cell function by up-regulating the expression of FoxP3, converting cytotoxic T cells to Treg cells to restrain immune response. Besides, TGF-β impairs NK function by down-regulation of NKG2D and NKp30, two surface receptors directing NK cells to eliminate abnormal cells. TGF-β impairs antigen presentation in DC cells by decreasing MHCII expression. TGF-β signaling pathway polarizes macrophages to the pro-tumorigenic M2 phenotype by increasing Snail, converts N1 neutrophils to an N2 phenotype by up-regulation of arginine, CCL2, CCL5, and facilitates expansion of MDSCs leading to enhanced immune tolerance.