Cracking the EGFR Code: Cancer Biology, Resistance Mechanisms, and Future Therapeutic Frontiers

Epidermal growth factor receptor (EGFR) plays a crucial role in tumorigenesis across multiple cancer types. EGFR mutations, overexpression, amplifications, dysregulated signaling, and impaired receptor downregulation drive cancer progression, particularly in non-small cell lung cancer, glioblastoma, colorectal cancer, gastric cancer, and head and neck cancers. Over the past decades, EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved patient outcomes. However, drug resistance inevitably arises through on-target mutations, activation of bypass signaling pathways, and disruptions in receptor trafficking and degradation. To overcome resistance, novel therapeutic strategies such as new generation of tyrosine kinase inhibitors, antibody-drug conjugates, and targeted protein degradation approaches like proteolysis-targeting chimeras are being actively explored. Additionally, combination therapies targeting parallel or compensatory pathways are being explored in mitigating drug resistance. Advances in genomic profiling and liquid biopsy technologies further enable personalized treatment strategies tailored to individual genetic backgrounds. In this review, we provide an overview of EGFR signaling and examine the landscape of EGFR mutations and currently available targeted therapies, while highlighting key resistance mechanisms. Furthermore, emerging strategies designed to overcome resistance are discussed, offering insights into future directions for EGFR-targeted cancer treatment. SIGNIFICANCE STATEMENT: Epidermal growth factor receptor (EGFR) is a key driver of tumorigenesis across multiple cancers, with overexpression, mutations, and amplifications promoting disease progression and therapeutic resistance. Despite the success of EGFR-targeted therapies, resistance remains a significant barrier to sustainable efficacy. This review provides an overview of EGFR biology and therapy, resistance mechanisms, and emerging new therapeutic strategies. A deeper understanding of these aspects is crucial for overcoming resistance and guiding the development of more effective and personalized cancer treatments.