Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is activated by ligand binding, overexpression, or mutation. It is well known for its tyrosine kinase-dependent oncogenic activities in a vari-ety of human cancers. A large number of EGFR inhibitors have been developed for cancer treatment, including monoclonal antibodies, tyrosine kinase inhibitors, and a vaccine. The EGFR inhibitors are aimed at inhibiting the activation or the activity of EGFR tyrosine kinase. How-ever, these agents have shown efficacy in only a few types of cancers. Drug resistance, both intrinsic and acquired, is common even in cancers where the inhibitors have shown efficacy. The drug resistance mechanism is complex and not fully known. The key vulnerability of cancer cells that are resistant to EGFR inhibitors has not been identified. Nevertheless, it has been increasingly recognized in re-cent years that EGFR also possesses kinase-independent oncogenic functions and that these noncanonical func-tions may play a crucial role in cancer resistance to EGFR inhibitors. In this review, both kinase-dependent and -independent activities of EGFR are discussed. Also dis-cussed are the mechanisms of actions and therapeutic activities of clinically used EGFR inhibitors and sus-tained EGFR overexpression and EGFR interaction with other receptor tyrosine kinases to counter the EGFR in-hibitors. Moreover, this review discusses emerging ex-perimental therapeutics that have shown potential for overcoming the limitation of the current EGFR inhibi-tors in preclinical studies. The findings underscore the importance and feasibility of targeting both kinase-dependent and-independent functions of EGFR to enhance therapeutic efficacy and minimize drug resistance.

Automated summary

EGFR is a receptor tyrosine kinase that can be activated by ligand binding, overexpression, or mutation. Various EGFR inhibitors have been developed for cancer treatment, but they only show efficacy in a few types of cancers and drug resistance is common. It has been increasingly recognized that EGFR also possesses noncanonical kinase-independent oncogenic functions, which may play a crucial role in cancer resistance to EGFR inhibitors.