Histone Methylation and Chromatin Remodeling in Non-Small Cell Lung Cancer: Mechanisms of Oncogenesis and Emerging Therapeutic Strategies

Lung cancer remains the leading cause of cancer-related death, and, despite significant advancements in targeted therapy and immunotherapy, survival for patients with advanced non-small cell lung cancer (NSCLC) remains poor. An emerging area of interest is the role of epigenetic modifiers in both the pathogenesis and treatment of NSCLC. Herein, we review a selected group of chromatin-modifying genes implicated in NSCLC, organized by their function as writers (KMT2A, SETD2, and EZH2), erasers (the KDM2, KDM5, and KDM6 demethylase families), and readers (the SWI/SNF subunits SMARCA4 and ARID1A). Writers deposit activating or repressive marks on histones to regulate gene transcription, erasers remove these marks, and readers reposition nucleosomes and control DNA accessibility. Dysregulation of these genes has been associated with tumor proliferation, metastasis, treatment resistance, and altered response to immune checkpoint blockade in NSCLC. Research within this topic is emerging, and these genes represent promising potential therapeutic avenues as well as potential biomarkers. Finally, we review the clinical trials involving targeting these genes available in the current literature. The number of NSCLC-specific trials remains limited, with the most active development in SMARCA2 inhibitors for SMARCA4-mutated tumors and EZH2 inhibitors given in tandem with PD-1 blockade. We hope this review is hypothesis-generating for ongoing investigation into the role of epigenetic modifiers in NSCLC and their potential to expand the therapeutic armamentarium available for this disease.