Elucidating the regulation of mitosis by BRAF V600E in lung cancer

阐明 BRAF V600E 对肺癌有丝分裂的调节

• 批准号: 8968080
• 负责人: Piro Lito
• 金额: $ 18万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-07 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968080
• 关键词: Affect; Aftercare; Anaphase; Antigens; BRAF gene; Biology; Bypass; CDC2 Protein Kinase; Cancer cell line; Cdc25C protein; Cell Line; Cell physiology; Cells; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Dependence; Dependency; Disease; Doctor of Philosophy; Drug resistance; Exhibits; Feedback; Funding; G2/M Transition; Gene Expression; Genes; Health; Human; Institution; Investigation; KRAS2 gene; Literature; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Medicine; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Mind; Mitosis; Mitotic; Modeling; Mutate; Mutation; Nature; Non-Small-Cell Lung Carcinoma; Nuclear; Oncogene Proteins; Oncogenes; PLK1 gene; Patient Care; Patients; Pharmaceutical Preparations; Phosphorylation; Play; Pre-Clinical Model; Principal Investigator; Process; Progressive Disease; Property; Proteins; Regulation; Reporting; Research; Research Project Grants; Resistance; Resources; Role; Scientist; Signal Transduction; Sister Chromatid; Site; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Translational Research; Tumor-Associated Process; United States; Work; Xenograft Model; anticancer research; base; cancer cell; cohesin; design; experience; gene function; improved; inhibitor/antagonist; innovation; killings; melanoma; mutant; next generation sequencing; novel; pre-clinical; programs; protein complex; repaired; research study; resistance mechanism; response; restoration; therapeutic target; tumor; tumor growth

 DESCRIPTION (provided by applicant): This application describes a five year mentored research project designed to transition the applicant to an independent scientist in the field of lung cancer research. This proposal will be conducted at Memorial Sloan Kettering Cancer Center (MSKCC) under the mentorship of Neal Rosen, MD, PhD, a world recognized leader in the field of targeted therapeutics in cancer and feedback regulation of intracellular signaling. Under the mentorship of Dr. Rosen, the principal investigator has previously described the process of tumor adaptation to RAF inhibitors in melanomas harboring a BRAF V600E mutation (Lito et al., Cancer Cell, 2012 and reviewed in Lito et al., Nature Medicine, 2013), or to MEK inhibitors in KRAS mutant cancers (Lito et al., Cancer Cell, 2014). The work in this proposal set out to investigate the mechanism of acquired resistance to RAF inhibitors in patient-derived models of BRAF V600E-mutant lung cancer. Preliminary findings identified an acquired deletion in the stromal antigen 2 gene (STAG2) after treatment with the RAF inhibitor dabrafenib. STAG2 is a component of cohesin, a protein complex that regulates the separation of sister chromatids during anaphase and plays a key role in mitosis. Based on this and other preliminary results, this proposal now aims to determine the role of ERK signaling in the regulation of mitosis in BRAF V600E-mutant lung cancer. We hypothesized that BRAF V600E regulates G2/M signaling in a STAG2 dependent manner and that STAG2 plays a role in the dependence of tumors on BRAF V600E. To test this, we will first determine if BRAF V600E regulates G2/M signaling in a panel of cell lines harboring this mutation. Then, we will determine if STAG2 is required for tumor formation by BRAF V600E in patient-derived models of lung cancer and if STAG2 modulates BRAF V600E-dependent signaling during G2/M. Finally, we will investigate if STAG2 is required for the sensitivity of BRAF V600E tumors to RAF inhibitor treatment and determine the mechanism by which this occurs. These efforts have the potential of identifying novel cellular functions regulated by BRAF V600E and/or cohesin proteins, as well as identifying rational therapeutic interventions that are impactful in the care of patients with lung cancer. Thi is an ideal project to transition the principal investigator towards an independent translational scientist because it builds on his previous experience to establish an independent research program at an institution with the available resources to conduct high impact translational research.

 描述（由申请人提供）：本申请描述了一个为期五年的指导研究项目，旨在将申请人转变为肺癌研究领域的独立科学家。该提案将在纪念斯隆凯特琳癌症中心 (MSKCC) 的 Neal Rosen 医学博士、哲学博士的指导下进行，Neal Rosen 是癌症靶向治疗和细胞内信号反馈调节领域世界公认的领导者。在 Rosen 博士的指导下，主要研究者之前描述了携带 BRAF V600E 突变的黑色素瘤中肿瘤对 RAF 抑制剂的适应过程（Lito 等人，Cancer Cell，2012，Lito 等人，Nature Medicine，2013 中进行了综述），或 KRAS 突变癌症中对 MEK 抑制剂的适应过程（Lito 等人，Cancer Cell，2014）。该提案的工作旨在研究患者衍生的 BRAF V600E 突变肺癌模型中对 RAF 抑制剂获得性耐药的机制。初步研究结果发现，在使用 RAF 抑制剂达拉非尼 (dabrafenib) 治疗后，基质抗原 2 基因 (STAG2) 出现了获得性缺失。 STAG2 是粘连蛋白的一个组成部分，粘连蛋白是一种蛋白质复合物，可调节后期姐妹染色单体的分离，并在有丝分裂中发挥关键作用。基于这一结果和其他初步结果，该提案现在旨在确定 ERK 信号在 BRAF V600E 突变型肺癌有丝分裂调节中的作用。我们假设 BRAF V600E 以 STAG2 依赖性方式调节 G2/M 信号传导，并且 STAG2 在肿瘤对 BRAF V600E 的依赖性中发挥作用。为了测试这一点，我们将首先确定 BRAF V600E 是否调节一组含有该突变的细胞系中的 G2/M 信号传导。然后，我们将确定在患者来源的肺癌模型中 BRAF V600E 形成肿瘤是否需要 STAG2，以及 STAG2 是否在 G2/M 期间调节 BRAF V600E 依赖性信号传导。最后，我们将研究 BRAF V600E 肿瘤对 RAF 抑制剂治疗的敏感性是否需要 STAG2，并确定发生这种情况的机制。这些努力有可能确定由 BRAF V600E 和/或粘连蛋白调节的新细胞功能，以及确定对肺癌患者的护理有影响的合理治疗干预措施。这是一个将首席研究员转变为独立转化科学家的理想项目，因为它建立在他以前的经验基础上，在拥有可用资源的机构建立一个独立的研究项目，以进行高影响力的转化研究。