College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
Int J Mol Sci. 2021 Oct 28;22(21):11701. doi: 10.3390/ijms222111701.
Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.
肺癌是男性和女性癌症死亡的主要原因，其中非小细胞肺癌（NSCLC）约占所有肺癌的 85%。在诊断时，肿瘤通常处于局部晚期或转移阶段，预后较差。NSCLC 包括腺癌、鳞状细胞癌和大细胞肺癌。由于铂类治疗以及过去十年开发的靶向治疗效果有限，以及大约一半的 NSCLC 病例缺乏突变检测，因此需要寻找新的治疗靶点。后者主要是由于缺乏突变检测。还需要新的治疗方法来增强 NSCLC 免疫疗法的效果。确定 NSCLC 亚型的分子特征，包括遗传和表观遗传变异，对于选择合适的治疗方法或治疗组合至关重要。表观遗传失调在肿瘤发生、肿瘤异质性和肿瘤对传统抗癌治疗的耐药性中起着关键作用。表观基因组调节是 NSCLC 的一种潜在治疗策略，很久以前就提出了这一策略，最近开始引起更多关注。组蛋白乙酰化和去乙酰化是最常研究的表观遗传修饰模式。几种组蛋白去乙酰化酶（HDAC）抑制剂（HDIs），如伏立诺他和帕比司他，在 NSCLC 的临床前和临床研究中显示出了希望。然而，仍需要对 NSCLC 中的 HDIs 进行进一步研究，以评估其抗肿瘤作用。另一种修饰形式，组蛋白甲基化，是组蛋白修饰中最被认可的模式之一。它可以在不同的基因座促进或抑制转录，因此在肺癌中发挥着相当复杂的作用。一些组蛋白甲基化修饰剂的活性发生了改变，表明它们具有致癌或肿瘤抑制作用。在这篇综述中，我们将讨论 NSCLC 中组蛋白修饰的模式，重点讨论表观遗传修饰在肿瘤进展和转移以及耐药性形成中的分子机制。然后，我们将探讨从 NSCLC 表观基因组研究中出现的治疗靶点，并提到正在进行的这些药物的临床试验。
