KRAS- and BRAF- Driven Lung Adenocarcinoma

编码有丝分裂信号通路组成部分的四个基因的突变已在 人类肺腺癌，包括EGFR、KRAS、HER2和BRAF。遗传模型展示了 KRAS、EGFR和BRAF的激活突变在这些肿瘤的发病机制中起一定作用。 这些数据表明，抑制这些癌相关蛋白功能的药物可能是重要的治疗药物。 这种疾病的病原体。这一点被EGFR抑制剂在肿瘤中的临床抗肿瘤活性所证实。 EGFR突变。突变的KRAS是这些病变中最常见的(在25%的腺癌中检测到)， 但不幸的是，目前还没有有效抑制这种癌蛋白的药物。这项提案的目标是 是抑制KRAS功能的治疗策略的发展。我们假设晚期肺脏 具有突变KRAS的腺癌仍然依赖于它的功能，它的作用是通过 一种或多种KRAS效应器蛋白。这些组织包括RAF、PI3KCA、RAL-GDS和其他组织。我们的 初步数据显示，肺腺癌细胞系的一部分对MEK的抑制敏感 激酶，英国皇家空军的下游目标。此外，KRAS和PI3KCA(编码 PI3K的P110α催化亚基突变)对MEK或PI3K的抑制都具有抗性，但 对两个靶点的联合抑制很敏感。我们假设肺腺癌是KRAS- 突变型和PI3KCA野生型将单独对MEK抑制敏感，其他肿瘤将 对MEK/MAPK和PI3K/AKT通路的联合抑制敏感。我们现在提议 检测突变的KRAS肺癌细胞系对KRAS及其效应分子表达的依赖性 分子，研究这些肿瘤依赖MEK和PI3K的机制，以及 确定MEK和PI3K/AKT抑制剂单独和 最终目标是开发一种治疗肺腺癌的策略。 依赖KRAS的肺腺癌的治疗。

Mutations in four genes that encode components of mitogenic signaling pathways have been identified in human lung adenocarcinomas,including the EGFR, KRAS, HER2, and BRAF. Genetic models demonstrate that the activating mutations of KRAS, EGFR, and BRAF play a role in the pathogenesis of these tumors. These data suggest that agents that inhibit the function of these oncoprpteins could be important therapeutic agents in this disease. This is borne out by the clinical antitumor activity of EGFR inhibitors in tumors with EGFR mutation. Mutant KRAS is the most common of these lesions (detected in 25% ofadenocarcinomas), but unfortunately there is currently no drug that effectively inhibits this oncoprotein. The goal of this proposal is the development of therapeutic strategies that inhibit KRAS function. We hypothesize that advanced lung adenocarcinomas with mutant KRAS are still dependent on its function and that its effects are mediated by one or more of the KRAS effector proteins. These include RAF, PI3KCA, RAL-GDSand others. Our preliminary data show that a subset of lung adenocarcinomacell lines is sensitive to inhibition of MEK kinase, the downstreamtarget of RAF. Furthermore, tumors in which both KRAS and PI3KCA (encoding the P110alpha catalytic subunit of PI3K) are mutated are resistant to inhibition of either MEK or PI3K but sensitive to combined inhibition of both targets. We hypothesize lung adenocarcinomasthat are KRAS- mutant and PI3KCA wild type will be sensitive to MEK inhibition alone, and that additional tumors will be sensitive to combined inhibition of both the MEK/MAPK and PI3K/AKT pathways. We propose now to determine the dependence of mutant KRAS lung cancer cell lines on expression of KRAS and its effector- molecules, investigate the mechanisms underlying the MEK and PI3K dependence of these tumors, and determine the biologic and potential therapeutic consequences of MEK and PI3K/AKT inhibitors, alone and in combination, in lung adenocarcinomas.The eventual goal is the development of a strategy for the treatment of KRAS-dependent lungadenocarcinoma.