CDK12 in Ovarian Cancer

CDK12 在卵巢癌中的作用

• 批准号: 9035009
• 负责人: LARRY M KARNITZ
• 金额: $ 38.4万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035009
• 关键词: Affect; Archives; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; Biochemical; C-terminal; Cancer Patient; Cancer cell line; Cell Cycle Progression; Cells; Chromatin; Cisplatin; Collection; Complex; Cyclin-Dependent Kinases; DNA Repair; Data; Defect; Disabled Persons; Disease; Gene Expression; Genes; Genetic Transcription; Human; Lesion; Malignant Neoplasms; Malignant neoplasm of ovary; Messenger RNA; Methylation; Modeling; Modification; Mutate; Mutation; Pathway interactions; Patient-Focused Outcomes; Patients; Phase III Clinical Trials; Phosphorylation; Phosphotransferases; Platinum; Platinum Compounds; Poly(ADP-ribose) Polymerases; Polyadenylation; Prevalence; Progression-Free Survivals; Protein Kinase; Proteins; Publishing; RNA Polymerase II; RNA Splicing; RNA polymerase II largest subunit; Recruitment Activity; Regulation; Relapse; Research Personnel; Role; Serous; Specimen; Transcript; Transcription Initiation; Tumor Biology; Woman; base; cancer cell; chemotherapy; homologous recombination; inhibitor/antagonist; innovation; insight; mRNA Precursor; member; neoplastic cell; novel; novel marker; novel therapeutics; ovarian neoplasm; public health relevance; recombinational repair; repaired; response; standard of care; tumor

 DESCRIPTION (provided by applicant): The cyclin-dependent kinase 12 (CDK12) gene is among the most frequent spontaneously mutated genes in high-grade serous ovarian cancers, the most lethal gynecological malignancy. As we have shown, these mutations disrupt the function of the kinase. Additionally, CDK12 often show loss of copy number in ovarian tumors. Taken together, these findings suggest that CDK12 is often disabled in ovarian cancer. Unlike other CDKs, CDK12 does not regulate cell cycle progression. Instead, CDK12 regulates the expression of a subset of human genes, including BRCA1 such that disabling CDK12 reduces the levels of BRCA1, which facilitates homologous recombination (HR) repair. Consistent with a decrease in BRCA1, disabling CDK12 in ovarian cancer cell lines disrupts HR, sensitizes cells to agents that induce lesions repaired by HR, and sensitizes cells to poly(ADP-ribose) polymerase (PARP) inhibitors, which are selectively toxic to cells with disabled HR. It remains unclear, however, whether CDK12 mutations or reduced CDK12 levels affect the responses of human ovarian tumors to PARP inhibitors that are currently in Phase 3 clinical trials. Additionally, our understanding of the regulation and biochemical roles of CDK12 remains incomplete. Recent studies showed that CDK12 phosphorylates Ser2 in the heptapeptide repeats of the C-terminal domain (CTD) of RBP1, the largest subunit of RNA polymerase II (RNAPII). This phosphorylation regulates multiple aspects of transcription by recruiting chromatin modifiers and remodelers, and facilitating mRNA splicing, 3' end cleavage, and polyadenylation. Despite this progress, however, it is not currently known how CDK12 is regulated, nor do we know whether CDK12 regulates gene expression solely by phosphorylation of Ser2 in the CTD of RBP1 or by phosphorylating other substrates. In this application we will to examine how CDK12 is regulated (Aim 1), evaluate how CDK12 regulates pre-mRNA splicing (Aim 2), and determine whether the expression levels of CDK12 pathway components correlates with patient outcomes in women with high-grade serous ovarian cancer treated with platinum-based therapy (Aim 3). Impact and Relevance: Collectively, these studies are relevant because they will 1) provide novel mechanistic insights into the regulation and biochemical roles of CDK12, a protein kinase with major impacts on tumor biology but whose mechanisms of action remain obscure; and 2) determine whether the CDK12 pathway is associated with responses to standard-of-care therapy and novel therapies for ovarian cancer.

 描述（由申请人提供）：细胞周期蛋白依赖性激酶12（CDK 12）基因是高级别浆液性卵巢癌（最致命的妇科恶性肿瘤）中最常见的自发突变基因之一。正如我们所展示的，这些突变破坏了激酶的功能。此外，CDK 12通常在卵巢肿瘤中表现出拷贝数的丢失。综上所述，这些发现表明CDK 12在卵巢癌中经常被禁用。与其他CDK不同，CDK 12不调节细胞周期进程。相反，CDK 12调节包括BRCA 1在内的人类基因子集的表达，使得CDK 12失活降低BRCA 1的水平，这有助于同源重组（HR）修复。与BRCA 1减少一致，卵巢癌细胞系中CDK 12的失活破坏了HR，使细胞对诱导HR修复病变的药物敏感，并使细胞对多聚腺苷酸敏感。（ADP-核糖）聚合酶（PARP）抑制剂，其对HR丧失的细胞具有选择性毒性。然而，CDK 12突变或CDK 12水平降低是否会影响人类卵巢肿瘤对PARP抑制剂的反应，目前正在进行3期临床试验。此外，我们对CDK 12的调节和生化作用的理解仍然不完整。最近的研究表明，CDK 12磷酸化RNA聚合酶II（RNAPII）的最大亚基RBP 1的C-末端结构域（CTD）的七肽重复序列中的Ser 2。这种磷酸化通过募集染色质修饰剂和重塑剂以及促进mRNA剪接、3'端切割和多腺苷酸化来调节转录的多个方面。然而，尽管取得了这一进展，目前尚不清楚CDK 12是如何调节的，我们也不知道CDK 12是否仅通过磷酸化RBP 1 CTD中的Ser 2或通过磷酸化其他底物来调节基因表达。在本申请中，我们将研究CDK 12是如何调节的（目的1），评估CDK 12如何调节前体mRNA剪接（目的2），并确定CDK 12通路组分的表达水平是否与接受铂类药物治疗的高级别浆液性卵巢癌患者的预后相关（目的3）。影响和相关性：总的来说，这些研究是相关的，因为它们将1）为CDK 12的调节和生化作用提供新的机制见解，CDK 12是一种对肿瘤生物学具有重大影响的蛋白激酶，但其作用机制仍不清楚; 2）确定CDK 12通路是否与卵巢癌标准治疗和新疗法的反应相关。