Dual target inhibitors based on EGFR: Promising anticancer agents for the treatment of cancers (2017-)

The EGFR family play a significant role in cell signal transduction and their overexpression is implicated in the pathogenesis of numerous human solid cancers. Inhibition of the EGFR-mediated signaling pathways by EGFR inhibitors is a widely used strategy for the treatment of cancers. In most cases, the EGFR inhibitors used in clinic were only effective when the cancer cells harbored specific activating EGFR mutations which appeared to preserve the ligand-dependency of receptor activation but altered the pattern of downstream signaling pathways. Moreover, cancer is a kind of multifactorial disease, and therefore manipulating a single target may result in treatment failure. Although drug combinations for the treatment of cancers proved to be successful, the use of two or more drugs concurrently still was a challenge in clinical therapy owing to various dose-limiting toxicities and drug-drug interactions caused by pharmacokinetic profiles changed. Therefore, a single drug targeting two or multiple targets could serve as an effective strategy for the treatment of cancers. In recent, drugs with diverse pharmacological effects have been shown to be more advantageous than combination therapies due to their lower incidences of side effects and more resilient therapies. Accordingly, dual target-single-agent strategy has become a popular field for cancer treatment, and researchers became more and more interest in the development of novel dual-target drugs in recent years. In this review, we briefly introduce the EGFR family proteins and synergisms between EGFR and other anticancer targets, and summarizes the development of potential dual target inhibitors based on wild-type and/or mutant EGFR for the treatment of solid cancers in the past five years. Additionally, the rational design and SARs of these dual target agents are also presented in detailed, which will lay a significant foundation for the further development of novel EGFR-based dual inhibitors with excellent druggability.