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.
Highlights
Relationship Between transforming growth factor β (TGF-β) Signaling and Cancer Therapy ResistanceCancer is a leading cause of death globally and there has been on-going efforts to find cures for it
To target TGF-β-mediated resistance to immunotherapy, several groups have tested the combination of TGF-β inhibitors with anti-PD-1/programmed death-ligand 1 (PD-L1) antibodies that were approved by the FDA for the treatment of multiple advanced cancers, including atezolizumab, durvalumab, and avelumab; results from these studies showed that combination treatment elicited higher anti-tumor activity in murine model and human cancer cell lines, such as breast cancer, colon cancer, squamous cell carcinoma (SCC) (Lan et al, 2018; Mariathasan et al, 2018; Tauriello et al, 2018; Dodagatta-Marri et al, 2019; Principe et al, 2019; Lind et al, 2020)
The aberrant activation of TGF-β signaling plays a complex role in tumor progression, especially in the development of resistance towards cancer therapy
Summary
Cancer is a leading cause of death globally and there has been on-going efforts to find cures for it. In advanced pancreatic ductal adenocarcinomas (PDAC), intact TGFβ/SMAD4 pathway facilitates cancer progression; in advanced prostate cancer, bone-borne TGF-β induces osteoclastogenesis and bone metastasis by activating chemokine (C-X-C motif) receptor 4 (CXCR4) (Bardeesy et al, 2006; Zhang et al, 2021) These studies provided concrete evidence for the tumor suppressive role of the TGF-β pathway in pre-malignant cells and oncogenic role in advanced cancers. Selective blockade of the expression of the short isoform by blocking TGF-β-induced alternative splicing of TAK1 may be potential avenue to overcome TGFβ-induced drug resistance (Tripathi et al, 2019) Another example of TGF-β signaling-mediated resistance was reported in HER2 targeted therapy for HER2-positive cancers. We will summarize studies that reveal how TGF-β signaling induces chemotherapy resistance (Figure 3)
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