Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Semin Cancer Biol. 2022 Aug;83:57-76. doi: 10.1016/j.semcancer.2020.11.006. Epub 2020 Nov 18.
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.
小细胞肺癌（SCLC）是一种具有高死亡率的肺癌特殊亚型。近年来，对 SCLC 基因组学的认识和免疫疗法的突破极大地扩展了现有知识和治疗方法。然而，与 SCLC 相关的挑战仍然是神秘莫测的。大多数针对 SCLC 中改变的信号通路的传统药物发现方法最终都以“药物发现的墓地”告终，这要求我们探索超越抑制细胞信号通路的新方法。表观遗传修饰长期以来被认为是几乎所有类型癌症（包括 SCLC）肿瘤发生的关键因素。过去十年，我们对 SCLC 中表观遗传修饰的理解呈指数级增长。本综述强调了表观遗传调控在获得肿瘤表型、转移、侵袭性、对化疗和免疫治疗的耐药性等方面的核心作用。还讨论了不同类型的表观遗传修饰（DNA/组蛋白甲基化或乙酰化），这些修饰可作为预测生物标志物，用于预后、治疗分层、神经内分泌谱系确定以及潜在 SCLC 治疗方法的开发。我们还回顾了在临床前和临床研究中正在研究的表观遗传靶点/表观遗传药物与一线化疗和免疫疗法联合应用的效果。总之，这些信息呈现了 SCLC 表观遗传学和表观遗传药物的全貌，有助于改善 SCLC 的预后。
