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TGFβ in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance
Allan M Johansen1, Steven D Forsythe2, Callum T McGrath1
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Abstract:
TGFβ is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.
Insights
Transforming growth factor beta (TGFβ) is crucial in cell regulation but promotes cancer growth and immunotherapy resistance. Inhibiting TGFβ may enhance cancer treatments, with ongoing clinical trials for pancreatic and colorectal cancers.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Transforming growth factor beta (TGFβ) is a key signaling pathway with a dual role in cell regulation, capable of inhibiting growth or promoting it in cancer.
- TGFβ is frequently upregulated in colorectal and pancreatic cancers, significantly impacting the tumor microenvironment, immune response, and promoting epithelial-mesenchymal transition.
Purpose of the Study:
- To review current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancers.
- To explore advances in improving the clinical efficacy of TGFβ-targeted combination therapies.
- To discuss the role of TGFβ signaling alterations and germline variants in personalizing cancer treatment.
Main Methods:
- Literature review of clinical trials involving TGFβ inhibitors.
- Analysis of TGFβ's role in cancer progression and therapeutic resistance.
- Discussion of personalized medicine approaches based on TGFβ pathway status.
Main Results:
- Upregulated TGFβ contributes to therapeutic resistance in certain cancers, particularly to immunotherapy.
- Inhibition of TGFβ has shown promise in reducing therapeutic resistance when combined with chemotherapy and immunotherapy.
- Several TGFβ inhibitor drugs are currently undergoing clinical trials for pancreatic and colorectal cancers.
Conclusions:
- Targeting the TGFβ pathway presents a promising strategy for overcoming therapeutic resistance in pancreatic and colorectal cancers.
- Combination therapies involving TGFβ inhibitors alongside chemotherapy or immunotherapy may enhance treatment efficacy.
- Personalizing treatment by considering TGFβ signaling alterations and germline variants is essential for improving outcomes in non-responsive patients.
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