KRAS- and BRAF- Driven Lung Adenocarcinoma

在有丝分裂信号通路的四个编码基因中的突变已经被鉴定， 人肺腺癌，包括EGFR、KRAS、HER 2和BRAF。遗传模型表明 KRAS、EGFR和BRAF的激活突变在这些肿瘤的发病机制中起作用。 这些数据表明，抑制这些癌蛋白功能的药物可能是重要的治疗药物。 在这种疾病的代理人。EGFR抑制剂在肿瘤中的临床抗肿瘤活性证实了这一点， EGFR突变。突变型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。这项提案的目的是 是开发抑制KRAS功能的治疗策略。我们假设晚期肺部 具有突变KRAS的腺癌仍然依赖于其功能，并且其作用是由 一种或多种KRAS效应蛋白。这些包括RAF，PI 3 KCA，RAL-GD和其他。我们 初步数据显示，肺腺癌细胞系的一个子集对MEK的抑制敏感， 激酶是RAF的下游靶点。此外，KRAS和PI 3 KCA（编码PI 3 KCA）两者均表达的肿瘤中， PI 3 K的P110 α催化亚基）突变对MEK或PI 3 K的抑制具有抗性， 对两种靶标的联合抑制敏感。We hypothesize假设lung肺adenocarcinoma腺癌that are KRAS- 突变体和PI 3 KCA野生型将对单独MEK抑制敏感，且额外的肿瘤将 对MEK/MAPK和PI 3 K/AKT途径的联合抑制敏感。我们现在建议， 确定突变型KRAS肺癌细胞系对KRAS及其效应子表达的依赖性， 分子，研究这些肿瘤的MEK和PI 3 K依赖性的机制， 确定单独使用MEK和PI 3 K/AKT抑制剂的生物学和潜在治疗后果， 最终的目标是发展一种治疗肺腺癌的策略， KRAS依赖性肺腺癌的治疗。

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.