Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer

总结 小细胞肺癌（SCLC）的特征是侵袭性生长、基因组异质性和快速转移。 对化疗产生耐药性。SCLC患者经常表现出对以下药物的初始临床应答： 化疗，包括临床标准的护理顺铂-依托泊苷方案，但最终屈服于 化疗难治性疾病最近的测序研究表明，小细胞肺癌是癌症发病率最高的肿瘤之一。 突变的癌症，但这些努力还没有确定靶向的“驱动”突变在化学敏感和 化疗难治性疾病使用一个无偏见的，高通量的细胞筛选的不同化学库，我们 已经鉴定出SCLC化学敏感性和化学难治性肿瘤细胞对以下抑制剂高度敏感： 一般的转录装置。特别是，我们观察到SCLC肿瘤细胞对 THZ 1是一种新发现的细胞周期蛋白依赖性激酶7（CDK 7）的共价抑制剂，其功能为 RNA聚合酶II（Pol II）。我们发现，这种转录脆弱性部分是由 关键超级增强子（SE）驱动的SCLC癌基因对转录抑制的敏感性。因此我们 假设在SE及其相关基因中发现的其他转录CDK的抑制可以 提供额外的治疗途径。为此，我们开发了结构启发的方法， 设计针对各种转录CDK的共价抑制剂。我们进一步假设， 来自化疗初治和化疗患者的增强子景观和基因表达谱的比较分析， 难治性原发性肿瘤将1）鉴定化学难治性肿瘤特异性的转录和表观遗传特征， 疾病，2）能够分组为临床相关亚型，和3）确定转录和表观遗传 依赖性特异于化学难治性疾病，可以使用转录CDK抑制剂“麻醉”。 由于肿瘤癌基因表达和化疗耐药性的变化已被证明会影响免疫系统， 因此，我们预期化疗难治性肿瘤也会表现出免疫细胞活化的变化， 和渗透。通过将我们的临床亚型分类扩展到肿瘤微环境，我们希望 找到肿瘤和免疫细胞基因表达程序，适用于小分子靶向， 目的是增强肿瘤免疫监视能力。最后，已知许多转录CDK 转录调节调节对DNA损伤剂的反应的关键途径， 我们将研究转录CDK抑制剂是否也可以与其他免疫疗法组合， 研究性SCLC疗法。

Summary Small cell lung cancer (SCLC) is characterized by aggressive growth, genomic heterogeneity, and rapid development of resistance to chemotherapy. SCLC patients frequently demonstrate initial clinical response to chemotherapy, including the clinical standard of care cisplatin-etoposide regimen, but eventually succumb to chemo-refractory disease. Recent sequencing studies have demonstrated that SCLC is one of the most highly mutated cancers, but these efforts have yet to identify targetable `driver' mutations in both chemo-sensitive and chemo-refractory disease. Using an unbiased, high-throughput cellular screen of a diverse chemical library, we have identified that SCLC chemo-sensitive and chemo-refractory tumor cells are highly sensitive to inhibitors of the general transcription apparatus. In particular, we observed that SCLC tumor cells were highly sensitive to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7) that functions as a co-factor for RNA polymerase II (Pol II). We found that this transcriptional vulnerability is conferred, in part, by the exquisite sensitivity of key super-enhancer (SE) -driven SCLC oncogenes to transcriptional inhibition. We therefore hypothesize that the inhibition of other transcriptional CDKs found at SEs and their associated genes could provide additional therapeutic avenues. For this purpose we have developed structure-inspired approaches for the design of covalent inhibitors targeting various transcriptional CDKs. We further hypothesize that comparative analysis of enhancer landscapes and gene expression profiles from chemo-naïve and chemo- refractory primary tumors will 1) identify transcriptional and epigenetic features specific to chemo-refractory disease, 2) enable grouping into clinically relevant subtypes, and 3) identify transcriptional and epigenetic dependencies specific to chemo-refractory disease that can be `drugged' using transcriptional CDK inhibitors. As changes to tumor oncogene expression and chemo-resistance have been shown to impact the immune compartment, we anticipate that chemo-refractory tumors will also exhibit changes in immune cell activation and infiltration. By extending our classification of clinical subtypes to the tumor microenvironment, we hope to find both tumor and immune cell gene expression programs that amenable to small molecule targeting with the goal of enhancing tumor immune surveillance capabilities. Lastly, as many transcription CDKs are known to transcriptionally regulate key pathways that modulate the response to DNA-damaging agents and immunotherapies we will investigate whether transcriptional CDK inhibitors may also be combined with other investigational SCLC therapies.