KRAS- and BRAF- Driven Lung Adenocarcinoma

编码有丝分裂信号通路成分的四个基因突变已在人肺腺癌中被发现，包括EGFR、KRAS、HER2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发挥作用。这些数据表明，抑制这些癌蛋白功能的药物可能是治疗这种疾病的重要药物。EGFR抑制剂在EGFR突变肿瘤中的临床抗肿瘤活性证实了这一点。突变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。该建议的目标是开发抑制KRAS功能的治疗策略。我们假设带有突变KRAS的晚期肺腺癌仍然依赖于其功能，并且其作用是由一种或多种KRAS效应蛋白介导的。这些包括RAF， PI3KCA， RAL-GDS和其他。我们的初步数据显示，肺腺癌细胞系的一个子集对RAF的下游靶点MEK激酶的抑制敏感。此外，KRAS和PI3KCA（编码PI3K的p110 α催化亚基）突变的肿瘤对MEK或PI3K的抑制都有抗性，但对两种靶点的联合抑制敏感。我们假设kras突变型和PI3KCA野生型肺腺癌仅对MEK抑制敏感，而其他肿瘤对MEK/MAPK和PI3K/AKT信号通路的联合抑制敏感。我们现在建议确定突变型KRAS肺癌细胞系对KRAS及其效应分子表达的依赖性，研究这些肿瘤对MEK和PI3K依赖的机制，并确定MEK和PI3K/AKT抑制剂单独或联合在肺腺癌中的生物学和潜在治疗效果。最终目标是开发一种治疗kras依赖性肺腺癌的策略。

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 oncoproteins 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% of adenocarcinomas), 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-GDS and others. Our preliminary data show that a subset of lung adenocarcinoma cell lines is sensitive to inhibition of MEK kinase, the downstream target 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 adenocarcinomas that 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 lung adenocarcinoma.