From receptor biology to therapy: importance of different EGFR mutations in the development of targeted cancer therapies.

Cancer is a leading cause of death globally, and traditional therapies including chemotherapy and radiotherapy are often constrained by systemic toxicity and lack of specificity. Thus, targeted therapies are the need of the hour to revolutionize cancer treatment by enhancing specificity and selectivity, and minimizing off-target effects. The epidermal growth factor receptor (EGFR) and its deletion mutant EGFRvIII exhibit pivotal roles in tumorigenesis, making them attractive targets across multiple cancers. Various targeted therapies, including small-molecule inhibitors, therapeutic antibodies, antibody-drug conjugates, and immunotherapies, are developed to target EGFR, EGFRvIII, and other clinically relevant EGFR mutations, namely L858R, C797S, and T790M. U.S. FDA has approved many of these agents as monotherapies or in conjunction with chemotherapy for treating lung, head and neck, and colorectal cancers; however, there are challenges. In this review, we discuss the role of EGFRvIII in driving aggressive tumor growth and highlight how effective targeting of EGFRvIII, and overcoming resistance mutations will be crucial to improve EGFR- and EGFRvIII-based therapies. The ongoing evolution of these interventions holds promise for long-term responses, reduced toxicity, and enhanced patient survival. Literature related to EGFR- and EGFRvIII-based therapies was searched systematically in PubMed, MEDLINE, Scopus, ScienceDirect, and Google Scholar up to June 2026.