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性研究项目，旨在将申请人转变为肺癌研究领域的独立科学家。这项建议将在纪念斯隆-凯特琳癌症中心(MSKCC)进行，由尼尔·罗森(Neal Rosen)医学博士指导。尼尔·罗森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Rosen博士的指导下，首席研究员之前已经描述了在含有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，癌症细胞，2012，并在Lito等人，自然医学，2013年中进行了综述)，或在KRAS突变癌症中对MEK抑制剂的适应过程(Lito等人，癌细胞，2014)。这项建议中的工作旨在研究患者来源的BRAF V600E突变肺癌模型中对RAF抑制剂的获得性耐药性的机制。初步研究发现，在RAF抑制剂达普拉非尼治疗后，间质抗原2基因(STAG2)发生了获得性缺失。STAG2是粘附素的一种成分，粘附素是一种蛋白质复合体，在有丝分裂的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，这项提议现在的目标是确定ERK信号在BRAF V600E突变肺癌有丝分裂调控中的作用。我们假设BRAF V600E以STAG2依赖的方式调节G2/M信号，STAG2在肿瘤对BRAF V600E的依赖中发挥作用。为了测试这一点，我们将首先确定BRAF V600E是否调节含有这种突变的一组细胞系中的G2/M信号。然后，我们将确定在患者来源的肺癌模型中，BRAF V600E是否需要STAG2来形成肿瘤，以及STAG2是否在G2/M期间调节BRAF V600E依赖的信号转导。最后，我们将调查是否需要STAG2来增强BRAF V600E肿瘤对RAF抑制剂治疗的敏感性，并确定其发生的机制。这些努力有可能确定受BRAF V600E和/或粘附素蛋白调控的新细胞功能，以及确定在肺癌患者护理中有效的合理治疗干预措施。这是一个将首席研究员转变为独立翻译科学家的理想项目，因为它建立在他之前的经验基础上，在一个拥有可用资源进行高影响力翻译研究的机构建立一个独立研究计划。

 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.