The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models

Abstract

Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.

Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer

“…Ge, a small-molecule TKI against EGFR, inhibits cancer growth mainly through targets the adenosine triphosphate binding sites in the cytoplasmic domain of EGFR [ 28 – 30 ]. Although Ge had been widely used in EGFR + NSCLC patients, unfortunately, it demonstrated little effectiveness in treating breast cancer [ 31 , 32 ].…”

Rethink of EGFR in Cancer With Its Kinase Independent Function on Board

“…Additionally, TKIs, especially the first generation of TKIs (Gefitinib and Erlotinib), are capable of causing dimerization of EGFR without significantly altering the level of EGFR protein (219–221) in a manner that is dependent on EGFR palmitoylation and independent of EGFR's kinase activity (222), which implicates that the TKI induced kinase inactivated EGFR dimer may gain new functions by recruiting novel interacting proteins. Further supports for the hypothesis that the kinase activity of EGFR is more critically involved in the proliferation than in the survival of cancer cells are offered by two studies: one is a study using rat models showing that inhibition of EGFR's kinase activity by TKI was able to inhibit growth but not the incidence of chemical or hormonal induced liver cancer (223), and consistently another study shows that the phosphorylation of the C-terminal tail (a hub domain that connects the kinase function of EGFR with its down-stream kinase dependent signaling cascades) is not required for the oncogenic function of EGFR mutant derived from lung cancer (178). Thus, we propose a new model of EGFR function: EGFR exists in two types of functional nodes, a kinase dependent functional node (the canonical functional node) that predominantly oversees cell proliferation and a kinase independent functional node that predominantly oversees cell survival, which is depicted by Figure 2.…”

Paclitaxel-loaded PLGA microspheres with a novel morphology to facilitate drug delivery and antitumor efficiency

“…Human hepatocellular carcinoma (HCC) which is mainly attributed to viral hepatitis and non-alcoholic steatohepatitis induced cirrhosis, 1 is among the top five most deadly cancers worldwide, and has an increasing incidence and a high mortality rate. 2,3 Despite recent progress in HCC patients treatment including hyperthermia therapy, 4 radiotherapy, 5 and chemotherapy, 6 the treatment to liver cancer are still remarkably limited because of high recurrence rates and conventional chemotherapy resistance. Among them, the chemotherapy plays an important role because most antitumor drugs are small molecules and their clearance from the tumor is rapid via the enhanced permeability and outward convective interstitial fluid flow effect.…”