Histologic Transformation in EGFR-Mutant Lung Adenocarcinomas: Mechanisms and Therapeutic Implications

SIMPLE SUMMARY: Despite being effective initially, almost all patients eventually develop resistance to EGFR-tyrosine kinase inhibitors (TKI). Changes in the histology of the tumor have been increasingly recognized as a critical mechanism of resistance to EGFR-directed therapies. This article summarizes histologic changes known to impart resistance to EGFR TKIs and discusses novel pathways to develop effective novel therapies. ABSTRACT: With the advent of potent EGFR tyrosine kinase inhibitors (TKIs), the treatment landscape of EGFR-mutant lung adenocarcinomas has changed drastically in recent years. However, the development of resistance to EGFR TKIs remains a critical barrier to improving survival in these patients. Histologic transformations to small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and the sarcomatoid phenotype have been increasingly recognized as important mechanisms of resistance. In this article, we summarize the known biological bases for such phenotypic switches in regard to EGFR TKIs and describe novel pathways that might be harnessed to develop effective novel therapies for patients with EGFR-mutant non-small cell lung cancers.