TGFβ in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance

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.

Figure 1:

Canonical and non-canonical TGFβ signaling pathway and therapeutics targetting TGFβ signaling. (Created with BioRender.com.)

Figure 2:

Overview of TGFβ release in the tumor microenvironment and the interplay between the tumor, EMT, immune evasion, and CAFs. (Created with Biorender.com.)