Mechanistic Determination of KRAS Lung Cancer Regression upon CRAF Suppression

项目总结 非小细胞肺癌(NSCLC)是世界范围内癌症死亡的主要原因。KRAS是一家 这种疾病的致癌驱动因素存在于约30%的非小细胞肺癌中。不幸的是，开发药物的努力 靶向突变的KRAS蛋白在很大程度上是不成功的，因为这两种单剂都抑制了效应器 事实证明，KRAS下游的路径或组合是无效的。因此，发展小说 KRAS驱动的NSCLC的治疗仍然是一个严重的未得到满足的需求领域。这件事的首要目标是 建议是剖析CRAF遗传消融如何导致退行性心脏病的机制基础 KRAS驱动的NSCLC。我们已经建立了一个由KRAS驱动的、带有可诱导CRAF的人NSCLC细胞系 在CRAF基因敲除后发生细胞凋亡的表达。该提案利用了这一系统，以及 生化和免疫学技术，以1)确定CRAF的结构域(S)负责介导 肿瘤消退，2)确定肿瘤消退所必需的下游效应，以及3)表征 CRAF缺失后肿瘤微环境的变化。改进了对这一点的机械性理解 这些目标的现象和成功执行将导致针对KRAS驱动的目标的新战略 肺癌，无论是单一疗法还是合理设计的联合疗法，以及潜在的 预测反应的生物标志物。维多利亚·王博士的导师是弗兰克·麦考密克博士，他是一位 RAS信号，并将受益于由迪恩·谢泼德博士、大卫博士组成的咨询委员会 Carbone、Matthew Krammel博士和Shiva Malek博士，他们将共同提供指导、合作 在癌症生物学、信号传递、免疫学和肺癌转化研究方面的专业知识。王医生有 还制定了一项全面的5年培训计划，该计划将利用以下网址提供的未偿还资源 加州大学旧金山分校(NIH资助在所有机构中排名第二)，纳入实验室培训，授课 课程、科学会议和职业发展机会，这些都将帮助她实现自己的成就 发展成为一名独立的、可翻译的肺癌研究人员的科学和职业目标。

PROJECT SUMMARY Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. KRAS is a major oncogenic driver of this disease and found in ~ 30% of all NSCLCs. Unfortunately, efforts to develop drugs that target mutant KRAS proteins have largely been unsuccessful, since both single agent inhibition of effector pathways downstream of KRAS or combinations have proven to be ineffective. Thus, developing novel therapies for KRAS-driven NSCLC remains an area with a critical unmet need. The overarching goal of this proposal is to dissect the mechanistic underpinning of how genetic ablation of CRAF induces regression of KRAS-driven NSCLC. We have generated a KRAS-driven, human NSCLC cell line with inducible CRAF expression that undergoes apoptosis upon CRAF knockdown. This proposal utilizes this system, along with biochemical and immunological techniques, to 1) identify the domain(s) of CRAF responsible for mediating tumor regression, 2) determine the downstream effectors necessary for tumor regression, and 3) characterize the changes within the tumor microenvironment upon CRAF loss. Improved mechanistic understanding of this phenomenon and successful execution of these aims will lead to novel strategies for targeting KRAS-driven lung cancers, either as monotherapy or rationally-designed combination therapy, as well as potential biomarkers predictive of response. Dr. Victoria Wang is mentored by Dr. Frank McCormick, a world expert in RAS signaling, and will also benefit from an advisory committee comprised of Dr. Dean Sheppard, Dr. David Carbone, Dr. Matthew Krummel, and Dr. Shiva Malek, who will collectively provide mentorship, collaboration and expertise in cancer biology, signaling, immunology, and lung cancer translational research. Dr. Wang has also formulated a comprehensive 5-year training plan that will leverage the outstanding resources available at UCSF (ranking second in NIH funding among all institutions), incorporating laboratory training, didactic coursework, scientific meetings and professional development opportunities that will assist her in achieving her scientific and career goals of developing into an independent, translational lung cancer investigator.