Elucidating the regulation of mitosis by BRAF V600E in lung cancer

 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）进行，由Neal罗森，MD，PhD指导，他是癌症靶向治疗和细胞内信号反馈调节领域的世界公认领导者。在罗森博士的指导下，主要研究者先前已经描述了在携带BRAF V600 E突变的黑素瘤中肿瘤适应RAF抑制剂的过程（Lito等人，Cancer Cell，2012，并在Lito等人，Nature Medicine，2013），或KRAS突变癌症中的MEK抑制剂（Lito et al. Cancer Cell，2014）。本提案中的工作旨在研究BRAF V600 E突变型肺癌患者来源模型中对RAF抑制剂获得性耐药的机制。初步研究发现，在用RAF抑制剂达拉菲尼治疗后，基质抗原2基因（STAG 2）中存在获得性缺失。STAG 2是一种蛋白质复合物，在有丝分裂后期调节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信号传导在BRAF V600 E突变型肺癌有丝分裂调节中的作用。我们假设BRAF V600 E以STAG 2依赖性方式调节G2/M信号传导，并且STAG 2在肿瘤对BRAF V600 E的依赖性中起作用。为了测试这一点，我们将首先确定BRAF V600 E是否在一组携带该突变的细胞系中调节G2/M信号传导。然后，我们将确定STAG 2是否是患者来源的肺癌模型中BRAF V600 E形成肿瘤所必需的，以及STAG 2是否在G2/M期间调节BRAF V600 E依赖性信号传导。最后，我们将研究BRAF V600 E肿瘤对RAF抑制剂治疗的敏感性是否需要STAG 2，并确定发生这种情况的机制。这些努力有可能鉴定由BRAF V600 E和/或粘附蛋白调节的新型细胞功能，以及鉴定对肺癌患者护理有影响的合理治疗干预措施。这是一个理想的项目，将主要研究者转变为一个独立的翻译科学家，因为它建立在他以前的经验，在一个拥有可用资源的机构建立一个独立的研究计划，进行高影响力的翻译研究。

 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.