Dissecting response and resistance to CDK4/6 inhibition in ER+ breast cancer

剖析 ER 乳腺癌对 CDK4/6 抑制的反应和耐药性

• 批准号: 8900637
• 负责人: Flora Luo
• 金额: $ 3.52万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900637
• 关键词: Breast Cancer Cell; Breast Cancer Patient; CDK4 gene; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Cell Cycle; Cell Cycle Inhibition; Cell Cycle Progression; Cells; Cessation of life; Clinical; Combined Modality Therapy; Cyclin-Dependent Kinase 4; DNA biosynthesis; Dependency; Development; E2F transcription factors; ESR1 gene; Estrogen Receptor Status; Estrogen Receptors; Estrogen receptor positive; Estrogens; Exhibits; G1 Phase; Genes; Genetic; Genomics; Goals; Growth; In Vitro; Ligand Binding Domain; Malignant Neoplasms; Mediating; Molecular; Mutation; Open Reading Frames; Pathway interactions; Phase; Publishing; Research; Resistance; Retinoblastoma Protein; S Phase; Signal Transduction; Testing; Therapeutic; Woman; Work; cdc Genes; clinical predictors; deprivation; drug efficacy; effective therapy; in vivo; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; mutant; novel; novel therapeutics; overexpression; prevent; public health relevance; resistance gene; resistance mechanism; response

 DESCRIPTION (provided by applicant): Despite recent advances in targeted cancer therapeutics, molecular determinants of response to these agents are often unclear and acquired resistance is widespread. Effective treatment of cancer patients necessitates an understanding of these mechanisms. Highly specific cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitors represent a novel and exciting class of targeted agents. CDK4/6 inhibitors prevent cell cycle progression from the first growth phase (G1) to the DNA synthesis (S) phase of the cell cycle. Although CDK4/6 inhibitors are the most advanced clinically in breast cancers that express the estrogen receptor (ER+), the mechanisms determining response and resistance are not fully characterized. Prior studies suggest that ER+ breast cancer cells that are resistant to estrogen deprivation therapy (a mainstay of treatment for this subtype) exhibit a dependency on CDK4 in vitro and in vivo. Furthermore, we have found that breast cancer cells expressing a constitutively active (and estrogen-independent) ER mutant are exquisitely sensitive to CDK4/6 inhibitor treatment. Therefore, we hypothesize that use of CDK4/6 inhibitors in breast cancer cells that are dependent on ER signaling might enrich for sensitivity to CDK4/6 inhibition. Most in vitro resistance studies on CDK4/6 inhibitors have only focused on cell cycle genes. It is unknown whether other pathways can also mediate resistance to CDK4/6 inhibition. The ultimate goal of the proposed research is to identify clinical predictors of response to CDK4/6 inhibitors and to preserve the efficacy of these targeted agents. To accomplish this goal, two proposed aims seek to (1) determine whether ER-mutant breast cancer cells are sensitive to CDK4/6 inhibition (2) systematically identify genes that can confer resistance to CDK4/6 inhibition in ER+ breast cancer.

 描述（由适用提供）：尽管靶向癌症治疗的最新进展，但对这些药物反应的分子决定剂通常不清楚，并且获得的耐药性很普遍。有效治疗癌症患者必须了解这些机制。高度特异性的细胞周期蛋白依赖性激酶4和6（CDK4和CDK6）抑制剂代表了一种新颖而令人兴奋的靶向剂类。 CDK4/6抑制剂可以防止细胞周期从第一生长阶段（G1）到细胞周期的DNA合成相。尽管CDK4/6抑制剂是表达雌激素受体（ER+）的乳腺癌中最先进的临床抑制剂，但确定反应和抗性的机制尚未完全表征。先前的研究表明，抗雌激素剥夺治疗具有抗性的ER+乳腺癌细胞（该亚型的治疗的主要治疗）表现出对CDK4的体外和体内的依赖性。此外，我们发现表达组成型活性（和雌激素独立）ER突变体的乳腺癌细胞对CDK4/6抑制剂治疗完全敏感。因此，我们假设在乳腺癌细胞中使用CDK4/6抑制剂的使用可能会富含对CDK4/6抑制剂的敏感性，仅关注细胞周期基因。尚不清楚其他途径是否还可以介导对CDK4/6抑制剂的耐药性。拟议研究的最终目标是确定对CDK4/6抑制剂反应的临床预测指标，并保留这些靶向药物的有效性。为了实现这一目标，两个提出的目标试图（1）确定ER突变乳腺癌细胞是否对CDK4/6抑制敏感（2）系统地识别可以在ER+乳腺癌中抑制CDK4/6的基因。