Epigenetic landscape of small cell lung cancer: small image of a giant recalcitrant disease

Abstract

Small cell lung cancer (SCLC) is a particular subtype of lung cancer with high mortality. Recent advances in understanding SCLC genomics and breakthroughs of immunotherapy have substantially expanded existing knowledge and treatment modalities. However, challenges associated with SCLC remain enigmatic and elusive. Most of the conventional drug discovery approaches targeting altered signaling pathways in SCLC end up in the 'grave-yard of drug discovery', which mandates exploring novel approaches beyond inhibiting cell signaling pathways. Epigenetic modifications have long been documented as the key contributors to the tumorigenesis of almost all types of cancer, including SCLC. The last decade witnessed an exponential increase in our understanding of epigenetic modifications for SCLC. The present review highlights the central role of epigenetic regulations in acquiring neoplastic phenotype, metastasis, aggressiveness, resistance to chemotherapy, and immunotherapeutic approaches of SCLC. Different types of epigenetic modifications (DNA/histone methylation or acetylation) that can serve as predictive biomarkers for prognostication, treatment stratification, neuroendocrine lineage determination, and development of potential SCLC therapies are also discussed. We also review the utility of epigenetic targets/epidrugs in combination with first-line chemotherapy and immunotherapy that are currently under investigation in preclinical and clinical studies. Altogether, the information presents the inclusive landscape of SCLC epigenetics and epidrugs that will help to improve SCLC outcomes.

Keywords: DNA methylation; Epigenetic modifications; Histone acetylation; Neuroendocrine carcinoma; Small cell lung cancer.

Figure 1:

Epigenetic landscape of SCLC genome is regulated at the DNA & histone level by multiple regulators. The prime features of this regulation involve modifications of basic chromatin unit ‘nucleosome’ an octamer of histone that works as a spool for DNA wrapping. The key post-translational modifications of histones mainly involves acetylation and methylation of lysine residues that controls chromatin transformations and regulates the expression of target genes (other modifications like sumoylation, phosphorylation, and ubiquitination, are not shown here). A number of chromatin modifier proteins are involved performing this task including readers, writers, and erasers (like HDACS, HATs, and methyltransferases). SCLC-specific key epigenetic genes that regulate the histone/DNA related epigenetic modifications have been reviewed and summarized in the illustration. Similar to writer, readers, and erasers, the overexpression of other factors like NFIB induces the chromatin relaxation (as shown in the lower side panel) and increases the accessibility of transcription factors to the DNA that ultimately induces the expression of SCLC related genes. Epigenetic drugs (HDACi: histone deacetylase inhibitors, HATi: histone acetyltransferase inhibitors, BETi: bromodomain and extra-terminal domain protein inhibitors, and inhibitors of methyltransferases) targets these chromatin modifiers.

Figure 2:

Epigenetic modifiers describing different SCLC subtypes. Key SCLC studies described in the text help to define the SCLC subtypes specific epigenetically regulated genes (as aligned on the circumference of each subtype). The proposed SCLC nomenclature was followed by Rudin et al., [41]. ASCL1, achaete-scute homologue 1; NE, neuroendocrine; NeuroD1, neurogenic differentiation factor 1; POU2F3, POU class 2 homeobox 3; YAP1, yes-associated protein 1.

Figure 3:

Three-dimensional structure of LSD1-CoREST complex showing the unique architecture of two different binding/active sites for the development of specific inhibitors of LSD1 with implications in SCLC. The same color scheme was used to represent linear domain organization (upper part) and subsequent domains in the three-dimensional cartoon model. The structural model was generated using PyMOL, and structure coordinates were taken from Protein Data Bank (PDB ID: 2IW5) [193].