肿瘤细胞治疗研究
英文原题：Pan-cancer multi-omics characterization of CDK12 and virtual screening of Vietnamese natural products for novel inhibitors.
我们的研究结果确立了CDK12作为癌症诊断、预后和免疫调节的可靠生物标志物，同时强调天然产物来源的骨架作为下一代CDK12抑制剂的有前景的先导化合物，可靶向野生型和耐药变体，并可能与新兴的免疫肿瘤学策略产生协同作用。
细胞周期蛋白依赖性激酶12（CDK12）是细胞周期相关转录程序的关键调控因子，作为多种恶性肿瘤中肿瘤发生的驱动因素和颇具前景的治疗脆弱性靶点，日益受到关注。在本研究中，我们将泛癌多组学分析与越南草药化合物库的计算筛选相结合，以鉴定同时靶向野生型CDK12及其耐药性C1039F变体的候选抑制剂。对TCGA和GTEx数据集的转录组学和蛋白质组学分析显示，与匹配的正常组织相比，CDK12在14种肿瘤类型中显著过表达。总生存期比较进一步表明，CDK12表达升高预示不同肾癌类型和胶质瘤的预后明显更差，而基因组分析确定卵巢癌是CDK12改变频率最高的恶性肿瘤。免疫解卷积分析显示，CDK12表达与内皮细胞和自然杀伤T细胞浸润之间存在强关联，提示CDK12失调与肿瘤免疫逃逸之间存在联系。作为对多组学研究的补充，我们进行了分子对接、分子动力学模拟和MM/PBSA自由能计算，以评估源自越南药用植物的天然化合物对两种CDK12变体的结合特征。包括来自Phaseolus vulgaris的2,3-Diepicastasterone（- 131.038 ± 23.572 kcal/mol），以及来自Eurycoma longifolia和Oryza sativa的化合物在内的多种植物化学物质表现出高度有利的结合亲和力和稳定的相互作用动力学，凸显其作为CDK12抑制剂开发的有前景的骨架。总体而言，我们的研究结果确立了CDK12作为癌症诊断、预后和免疫调节的可靠生物标志物，同时强调天然产物来源的骨架作为下一代CDK12抑制剂的有前景的先导化合物，可靶向野生型和耐药变体，并可能与新兴的免疫肿瘤学策略产生协同作用。
Cyclin-dependent kinase 12 (CDK12), a key regulator of cell-cycle-linked transcriptional programs, has gained increasing attention as a driver of tumorigenesis and a promising therapeutic vulnerability across diverse malignancies. In this study, we combined pan-cancer multi-omics profiling with a computational screen of a Vietnamese medicinal herbs compound library to identify candidate inhibitors targeting both wild-type CDK12 and its drug-resistant C1039F variant. Transcriptomic and proteomic analyses of TCGA and GTEx datasets revealed significant CDK12 overexpression in 14 tumor types compared with matched normal tissues. Overall survival comparisons further indicated that elevated CDK12 expression predicts markedly poorer outcomes in different renal cancer types and glioma, whereas genomic profiling identified ovarian cancer as the malignancy with the highest frequency of CDK12 alterations. Immune deconvolution analyses showed strong associations between CDK12 expression and infiltration by endothelial cells and natural killer T cells, suggesting a link between CDK12 dysregulation and tumor immune evasion. Complementing the multi-omics investigation, molecular docking, molecular dynamics simulations, and MM/PBSA free-energy calculations were conducted to evaluate the binding profiles of natural compounds derived from Vietnamese medicinal plants against both CDK12 variants. Several phytochemicals including 2,3-Diepicastasterone from Phaseolus vulgaris (- 131.038 ± 23.572 kcal/mol), as well as compounds from Eurycoma longifolia and Oryza sativa-exhibited highly favorable binding affinities and stable interaction dynamics, highlighting them as promising scaffolds for CDK12 inhibitor development. Collectively, our findings establish CDK12 as a robust biomarker for cancer diagnosis, prognosis, and immune modulation, while highlighting natural-product-based scaffolds as promising leads for next-generation CDK12 inhibitors targeting both wild-type and resistant variants, potentially synergizing with emerging immuno-oncology strategies.
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