Targeting receptor tyrosine kinases in gastric cancer

Abstract

Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.

Keywords: Receptor tyrosine kinases, Gastric cancer, Epidermal growth factor receptor, Trastuzumab, Cetuximab, Lapatinib, Panitumumab, Erlotinib, Bevacizumab

Core tip: Since the finding of receptor tyrosine kinases (RTKs) about thirty years ago, its functions have been examined over the years as key regulators of proliferation, differentiation, and metastasis. Several RTKs are activated in advanced gastric cancer (AGC) and various RTK inhibitors have been developed as tailored therapy. The results of recent clinical trials evaluate the effectiveness of targeting RTKs. Unfortunately, recent progress in the development of RTK-targeted therapy for AGC patients has been modest. To provide maximal therapeutic benefits, well-designed clinical trials and combinations with appropriate drugs are required. In addition, new predictive biomarkers are immediately obliged to guide the selection of a drug-sensitive patients’ population.