KRAS- and BRAF- Driven Lung Adenocarcinoma

KRAS 和 BRAF 驱动的肺腺癌

• 批准号: 8291121
• 负责人: NEAL X ROSEN
• 金额: $ 34.57万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8291121
• 关键词: Adenocarcinoma; Adenocarcinoma Cell; Affect; Animals; Antibodies; Apoptosis; BH3 Domain; BRAF gene; Bad protein; Biological Models; Breast Cancer Treatment; Cancer Etiology; Cancer cell line; Catalytic Domain; Cell Line; Cells; Cessation of life; Clinic; Clinical; Complex; Cytostatics; Data; Dependence; Development; Disabled Persons; Disease; ERBB2 gene; Elements; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Event; Feedback; Gene Mutation; Genes; Genetic Models; Goals; Growth; Growth Factor; Human; In Vitro; Individual; KRAS2 Gene Mutation; KRAS2 gene; Knowledge; Lesion; Lung Adenocarcinoma; MAP Kinase Gene; MAPK phosphatase; MEK inhibition; MEKs; Maintenance; Malignant neoplasm of lung; Mediating; Modeling; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogene Proteins; Output; PI3K/AKT; PIK3CA gene; PIK3CG gene; PTEN gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenocopy; Phenotype; Phosphotransferases; Play; Pre-Clinical Model; Proliferating; Proteins; Proto-Oncogene Proteins c-akt; RAS inhibition; Reagent; Refractory; Resistance; Role; Signal Pathway; Signal Transduction; Stromal Neoplasm; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Translations; Tumor Cell Line; Western World; Work; Xenograft Model; angiogenesis; base; cancer cell; design; genetic profiling; human MAP3K1 protein; in vivo; inhibitor/antagonist; kinase inhibitor; mouse model; mutant; neoplastic cell; patient population; ral Guanine Nucleotide Exchange Factor; small hairpin RNA; therapeutic development; tissue culture; treatment strategy; tumor

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.

已在人肺腺癌中鉴定了编码促有丝分裂信号传导通路组分的四种基因的突变，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这种疾病的重要治疗药物。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。该提案的目标是开发抑制KRAS功能的治疗策略。我们推测，晚期肺腺癌与突变KRAS仍然依赖于其功能，其影响是由一个或多个KRAS效应蛋白介导的。这些包括RAF，PI 3 KCA，RAL-GDS等。我们的初步数据表明，肺腺癌细胞系的一个子集是敏感的MEK激酶，RAF的下游目标的抑制。此外，其中KRAS和PI 3 KCA（编码PI 3 K的P110 α催化亚基）都突变的肿瘤对MEK或PI 3 K的抑制具有抗性，但对两种靶点的联合抑制敏感。我们假设KRAS突变型和PI 3 KCA野生型肺腺癌对单独的MEK抑制敏感，并且其他肿瘤对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及其效应分子表达的依赖性，研究这些肿瘤的MEK和PI 3 K依赖性的机制，并确定MEK和PI 3 K/AKT抑制剂单独和组合在肺腺癌中的生物学和潜在治疗后果。最终的目标是开发KRAS依赖性肺腺癌的治疗策略。