Mechanistic Targeting of Lung Cancer

肺癌的机械靶向

• 批准号: 7337851
• 负责人: Lucy M Anderson
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/7337851
• 关键词: Mechanistic; Targeting; Lung; Cancer

Lung cancer is the most common human neoplasm in the U.S. and, increasingly, in much of the world. While smoking is known to be the major etiological factor, the causative cellular and molecular mechanisms are complex and not well understood. Currently, we are focusing on two aspects of causation and behavior of adenocarcinoma, the most common form of lung cancer: the role of the K-ras gene; and contributions of a signaling pathway triggered by the ErbB3 receptor. The oncogene K-ras is often mutated in adenocarcinoma of the lung (as well as other common carcinomas), but the wild-type form is tumor suppressive. Important questions, then, are: why is mutant K-ras actively oncogenic? How is wild-type K-ras tumor suppressive? Answers to these questions could aid in prevention of up to 50 percent of human lung adenocarcinomas, and an even higher percentage of cancers of the colon and pancreas. We have found that transfection of mutant K-ras in lung epithelial cells causes increases in reactive oxygen species and DNA damage. High levels of ROS are also associated with DNA damage and malignant phenotype in human lung adenocarcinoma cell lines. Also mutant K-ras appears to downregulate peroxiredoxins, that are critical for peroxide regulation. These results support use of antioxidants for prevention/intervention of lung cancer. With regard to mechanisms of regulation of wild-type K-ras in nontransformed lung epithelial cells, conditioned medium from growth-arrested cells activates K-ras and reduces cell growth rate, and specific inhibitor studies implicate the epidermal growth factor receptor. Characterization of this role of the EGFR is in progress. Preliminary results indicate that alternate pathways from EGFR via the adaptor Grb2 may lead to growth arrest (via K-ras) or mitosis (via PI3kinase). Understanding of control of a toggle-switch role for the EGFR is critical.In the second aspect of this project, the majority of human and mouse lung adenocarcinoma cell lines, but not nontransformed cells, express the ErbB3 receptor, which signals through phosphatidylinositol 3-kinase, Akt, GSK3beta, and cyclin D1 to stimulate the cell cycle and also cell invasiveness and migration. These behaviors can be blocked with siRNA to ErbB3 or the several Akt isoforms. Thus, siRNA treatment may be an approach to therapy. siRNA to ErbB3 or Akt markedly suppressed the growth of humnan lung adenocarcinoma xenografts, promising novel therapeutic potential. This result has been confirmed in a second, more extensive experiment, and a third series that will control for non-specific effects is in progress.

肺癌是美国最常见的人类肿瘤，而且在世界上越来越多。虽然已知吸烟是主要的病因因素，但致病性细胞和分子机制是复杂的，尚不清楚。目前，我们着重于腺癌的因果关系和行为的两个方面，腺癌是肺癌的最常见形式：K-RAS基因的作用； ERBB3受体触发的信号通路的贡献。癌基因K-RAS通常在肺腺癌（以及其他常见的癌）中突变，但野生型形式是抑制肿瘤的。那么，重要的问题是：为什么突变k-ras会主动致癌？野生型K-Ras肿瘤如何抑制？这些问题的答案可以有助于预防多达50％的人类肺腺癌，而结肠和胰腺的癌症比例更高。我们发现，在肺上皮细胞中突变K-RAS的转染会导致活性氧和DNA损伤增加。高水平的ROS也与人肺腺癌细胞系中的DNA损伤和恶性表型有关。同样，突变的K-RAS似乎下调过氧化物毒素，这对于过氧化物调节至关重要。这些结果支持使用抗氧化剂预防/干预肺癌。关于非转化的肺上皮细胞中野生型K-RAS调节的机制，从生长降落的细胞中调节培养基会激活K-RAS并降低细胞生长速率，并且特定的抑制剂研究暗示了表皮生长因子受体。 EGFR的这种作用的表征正在进行中。初步结果表明，从EGFR通过适配器GRB2的替代途径可能导致生长停滞（通过K-RAS）或有丝分裂（通过PI3Kinase）。理解对EGFR的拨动切换作用的控制至关重要。在该项目的第二个方面，大多数人和小鼠肺腺癌细胞系，但没有未经转化的细胞表达ERBB3受体，它们通过磷脂酰辛糖醇3-基因酶，AKT，GSK3BETA和迁移的蜂窝蛋白和cyclations carteriestion and Clincations theclations the Clincations the ERBB3受体。这些行为可以用siRNA对ERBB3或几种AKT同工型阻塞。因此，siRNA治疗可能是一种治疗方法。 ERBB3或AKT的siRNA明显抑制了洪南肺腺癌异种移植物的生长，有希望的新型治疗潜力。该结果已在第二个更广泛的实验中得到证实，并且将控制非特异性效应的第三个系列。