Abstract
Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFβR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFβR inhibitor-based clinical trials on pancreatic cancer are reviewed.
Highlights
Receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) are transmembrane proteins expressed on the cell membrane, the structure of which includes the ligand binding domain, the transmembrane helix outside the cell membrane, and the area containing message regulation, tyrosine/serine/threonine kinase domain and C terminal tail [1,2]
Compared to the group of standard gemcitabine in combination with placebo, patients received with standard gemcitabine plus erlotinib (100 or 150 mg/d orally) exhibited improved overall survival (OS) (p = 0.038; hazard ratio 0.82; 95% CI 0.69 to 0.99) and progression free survival (PFS) (p = 0.04; hazard ratio 0.77; 95% CI 0.64 to 0.92)
Based on the fact that most mutations, such as SMAD4 and KRAS, are a downstream signaling factor of TGFβR, and the fact that the mutations of TGFβR accounts for 4–7% of pancreatic cancers [90,91], it can be observed that the formation of pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) is mostly driven by the paracrine or autocrine manner of TGF-β
Summary
Receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) are transmembrane proteins expressed on the cell membrane, the structure of which includes the ligand binding domain, the transmembrane helix outside the cell membrane, and the area containing message regulation, tyrosine/serine/threonine kinase domain and C terminal tail [1,2]. Once bound to the corresponding substrate, the tyrosine kinase domain (in the case of RTKs) and serine/threonine domain (in the case of TGFbR) will be activated, and initiate the downstream signaling axis, regulating physiological responses such as cell growth, morphology, and metabolism [1,2] (Figure 1). Since they are highly sensitive and have characteristics of initiating signal cascades, the regulation of these receptors is tightly controlled. Kindler et al [20] Gonçalves et al
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