The Use of Epidermal Growth Factor Receptor Type 2-Targeting Tyrosine Kinase Inhibitors in the Management of Epidermal Growth Factor Receptor Type 2-Positive Gastric Cancer: A Narrative Review

Abstract

Gastric cancer (GC), including gastroesophageal junction cancer (GEJC), continues to be one of the most frequently diagnosed neoplasms globally. Moreover, GC/GEJC is a principal cause of neoplasm-related fatalities. Early-stage GC/GEJC has a favorable five-year overall survival (OS) rate with surgical resection. However, the vast majority of patients present with advanced inoperable or metastatic disease with a very unfavorable five-year OS rate. Such patients are left with very limited therapeutic options, such as systemic chemotherapy, targeted therapy, and immunotherapy, all of which can be performed as monotherapy or in various combinations. The molecular profiling of GC has revealed several personalized therapeutic vulnerabilities, one of which is the expression of epidermal growth factor receptor type 2 (EGFR2, also known as HER2). HER2 overexpression or amplification is present in a fair subset of patients with GC/GEJC and has been shown to correlate with poor clinicopathological prognostic outcomes. Generally, treatment schemes to tackle HER2 in HER2-positive GC/GEJC comprise the use of anti-HER2 monoclonal antibodies or HER2-targeting tyrosine kinase inhibitors (TKIs). In this study, we engage in a narrative review of the available phase II and III literature on the efficacy and safety of HER2-targeting TKIs in the management of HER2positive GC/GEJC.

Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy

“…Hydroxychloroquine, verteporfin, and clarithromycin are still under clinical investigations [NCT04524702, NCT03774472, NCT03067051, NCT03033225, NCT04302324, NCT04063189, NCT02542657, NCT03031483, NCT00461084]. 3-Methyladenine, Lys05, 7-methyl-5-phenylpyrazolo[4,3- e ]tetrazolo[4,5- b ][ 1 , 2 , 4 ]triazine sulfonamide derivatives, miconazole and α –Hederin deserve for attention in a group of autophagy inhibitors undergoing preclinical trials [ 49 – 53 ]. In our study, we checked the concentrations of important proteins engaged in autophagy and we proved that Beclin-1 concentration was dependent on the chemotherapeutic agent dose.…”

“…Human epidermal growth factor receptor 2 (HER2) molecular pathway plays a significant role in the etiopathogenesis of many types of cancer and anti-HER2 therapy represents an important approach in targeted anticancer treatment [ 1 ]. HER2 receptors belong to the EGFR/HER family and are involved in the signaling, cell growth and differentiation of cells [ 2 ]. It was discovered that approximately 7–34% of patients with gastroesophageal cancer and 25–30% with breast cancer have overexpression or amplification of the HER2 gene [ 3 ].…”

“…Targeted agents in the group of HER2 inhibitors are still studied and different strategies are taken into account. Monoclonal antibodies (trastuzumab and pertuzumab) and tyrosine kinase inhibitors are commonly used in treatment of cancer with overexpressed HER2 [ 2 , 4 ]. Trastuzumab is a humanized monoclonal antibody that attaches to the extracellular binding domain of the HER2 receptor.…”

Apatinib exhibits synergistic effect with pyrotinib and reverses acquired pyrotinib resistance in HER2-positive gastric cancer via stem cell factor/c-kit signaling and its downstream pathways

“…Although clinical trials for GC treatment have continued to emerge, most of them have failed [2]. Among the molecular targets studied, human epidermal growth factor receptor 2 (HER2) is the most widely used, and its clinical significance has been clearly described.…”