Epigenetic reprogramming in small cell lung cancer

Abstract

Small cell lung cancer (SCLC), a highly lethal lung cancer sub-type with distinct neuroendocrine-like features, accounts for 10%–15% of all lung cancers. The overall 5-year survival rate remains less than 10%. SCLC is characterized by early metastasis, thus minimizing the potential patient benefits of surgery. In recent decades, the first-line treatment for SCLC has remained chemotherapy combining etoposide and cisplatin (E/P). Despite high rates of response to E/P treatment, SCLC eventually relapses and is almost universally resistant to treatment at recurrence, thus making SCLC a recalcitrant malignancy. Moreover, the limited knowledge regarding the molecular mechanisms underlying SCLC metastasis and resistance greatly hinders improvements in overall SCLC survival. To better understand the molecular mechanisms of SCLC and discover potential therapeutic targets, extensive efforts have continued for decades. Recently, several studies have implicated epigenetic modifications, including histone modifications, DNA methylation, and chromatin accessibility, in SCLC. NFIB has been documented to promote SCLC metastasis through a widespread increase in chromatin accessibility1. Of particular note, one recent study has indicated that KMT2C deficiency promotes SCLC metastasis through DNMT3A-mediated epigenetic reprogramming involving both histone and DNA hypomethylation2. These studies have revealed that epigenetic reprogramming plays an important role in SCLC. In this review, we summarize and discuss the advances in basic and translational research in SCLC, which have revealed the functional and targetable roles of epigenetic modifications during tumorigenesis, metastasis, and chemoresistance.