Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

Abstract

The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/ HER3, and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions, including differentiation, proliferation, survival, and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non-malignant cholangiopathies is far from complete. Current knowledge suggests a role for epidermal growth factor receptor (EGFR) in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently demonstrated in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti-ErbB therapies were efficient only in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. (HEPATOLOGY 2017; 00:000-000). ErbB/HER FamilyThe ErbB family of receptor tyrosine kinases comprises epidermal growth factor (EGF) receptor (EGFR; ErbB1/HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4; Fig. 1). These plasma membrane receptors are composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with a conserved tyrosine kinase (TK) domain, with the exception of ErbB3 which holds an inactive TK domain. They bind specific ligands belonging to the EGF family, with the exception of ErbB2 which has no known ligand. Thus, ErbB2 and ErbB3 are activated through heterodimerization with other family members. ErbB ligands are produced as transmembrane precursors and processed

The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma

“…Treatment of CCA patients remains challenging despite the identification of molecular pathways with high therapeutic potential such as EGFR (5)(6)(7)27). Although antibodies or TKI against EGFR have shown efficacy in preclinical studies (27)(28)(29), they did not provide significant improvement of global survival in clinical trials in CCA (9)(10)(11)(12)(13)(14). Here, we highlight resistance mechanisms whereby CCA cells evade EGFR inhibition.…”

“…In addition, dysregulations of EGFR expression and signaling have been associated with tumor progression and poorer prognosis in CCA patients (7,8). However, despite EGFR attractive position as a molecular target for therapy, several independent clinical trials have reported very poor responses in patients with CCA treated with different small tyrosine kinase inhibitors (TKI) and monoclonal antibodies designed to specifically target EGFR (9)(10)(11)(12)(13)(14).…”

“…Unfortunately, little is known about the factors that limit anti-EGFR responsiveness in CCA. Besides genetic modifications, such as KRAS mutations that determine the lack of response to EGFR TKI, no other mechanisms that could explain the ability of CCA tumor cells to develop adaptive behavior to escape from anti-EGFR treatment have been investigated (14). Thus, in the present work, we aimed to decipher the molecular mechanisms underlying the nonresponse of CCA cells to prolonged EGFR inhibition.…”

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

“…All these combinations showed enhanced inhibition both in vitro and in vivo. At the clinical level, anti‐EGFR therapies have been the most studied, either as single agents or in combination regimens . However, although they showed efficacy in preclinical studies, they did not provide significant improvement in overall survival in phases II and III clinical trials .…”

“…At the clinical level, anti‐EGFR therapies have been the most studied, either as single agents or in combination regimens . However, although they showed efficacy in preclinical studies, they did not provide significant improvement in overall survival in phases II and III clinical trials . Interestingly, a recent phase Ib study showed longer median overall survival in iCCA patients treated with pulsatile erlotinib combined with chemotherapy compared to patients treated with standard chemotherapy alone, suggesting an effect for pulsatile administration of anti‐EGFR …”