Emerging Molecular Dependencies of Mutant EGFR-Driven Non-Small Cell Lung Cancer

Epidermal growth factor receptor (EGFR) mutations are the molecular driver of a subset of non-small cell lung cancers (NSCLC); tumors that harbor these mutations are often dependent on sustained oncogene signaling for survival, a concept known as oncogene addiction. Inhibiting EGFR with tyrosine kinase inhibitors has improved clinical outcomes for patients; however, successive generations of inhibitors have failed to prevent the eventual emergence of resistance to targeted agents. Although these tumors have a well-established dependency on EGFR signaling, there remain questions about the underlying genetic mechanisms necessary for EGFR-driven oncogenesis and the factors that allow tumor cells to escape EGFR dependence. In this review, we highlight the latest findings on mutant EGFR dependencies, co-operative drivers, and molecular mechanisms that underlie sensitivity to EGFR inhibitors. Additionally, we offer perspective on how these discoveries may inform novel combination therapies tailored to EGFR mutant NSCLC.

Automated summary

Mutant EGFR is a molecular driver of non-small cell lung cancer, and tumors with these mutations often rely on sustained oncogene signaling. While inhibiting EGFR with tyrosine kinase inhibitors has shown clinical benefits, resistance remains a challenge. The genetic mechanisms underlying EGFR dependency and factors allowing tumor cells to escape this dependency are still not fully understood.