Targeting a non-canonical RAS-driven pathway in pancreatic cancer

靶向胰腺癌中非经典 RAS 驱动的通路

• 批准号: 8833253
• 负责人: DAVID A CHERESH
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833253
• 关键词: Apoptosis; Apoptotic; Attention; Cancer Patient; Cell Cycle; Cell Cycle Progression; Cell Cycle Stage; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Combined Modality Therapy; Complex; DNA Damage; Diagnosis; Family member; Fluorouracil; Genetic; Genetic Transcription; Genotoxic Stress; Goals; Growth; Growth Factor; Individual; Integrins; Ionizing radiation; KRAS2 gene; Lead; Link; MAP Kinase Gene; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Manuscripts; Medicine; Mitochondria; Mitogen-Activated Protein Kinase Inhibitor; Mitosis; Mitotic; Mitotic Spindle Apparatus; Mitotic spindle; Mutation; Nature; Neoplasm Metastasis; Oncogenic; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Proteins; Radiation Tolerance; Radiation-Sensitizing Agents; Reporting; Resectable; Role; Serine; Signal Pathway; Signal Transduction; Therapeutic; abstracting; gemcitabine; improved; in vivo; innovation; migration; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; pancreatic cancer cells; pancreatic neoplasm; prevent; radiation effect; radiosensitive; response; standard care; success; therapeutic target; therapy resistant; tumor growth; tumor progression; tumorigenesis

Project Summary/Abstract Activating K-RAS mutations occur in >95% of patients with advanced pancreatic cancer, and recent studies identify CRAF as a kinase required for tumorigenesis downstream of oncogenic K-RAS. Although CRAF kinase activity is traditionally linked to tumor progression via activation of MAPK signaling, we have focused our attention on two non-canonical CRAF pathways which are independent of CRAF catalytic activity and activation of MAPK. Several years ago, we established that CRAF phosphorylation on serine 338 (pS338) drives CRAF translocation to the mitochondria where it forms a complex with and inactivates the pro-apoptotic kinase ASK1 to promote cell survival. In a new manuscript in press at Nature Medicine, we now report that CRAF pS338 also forms a complex with the cell cycle kinase Plk1 at the mitotic spindle to impact cell cycle progression. Accordingly, genetic or allosteric inhibition of this serine on CRAF drives both apoptosis and mitotic arrest that is independent of the MAPK pathway and not observed with inhibitors of MAPK signaling. Our overall objective is therefore to target CRAF function and exploit its role in both cell survival and mitotic progression, in order to develop novel therapeutic approaches for pancreatic cancer patients. The proposed studies will define how these two unique MAPK-independent functions of CRAF contribute to progression and metastasis of pancreatic cancer driven by oncogenic K-RAS. In Aim 1 we determine the mechanisms by which the non-canonical CRAF pS338 pathway is activated in the unique genetic context of pancreatic cancer. Specifically, we will focus on how both K-RAS and PAK regulate CRAF pS338, since these molecules are known to be dysregulated in pancreatic cancer. The goal of Aim 2 is to evaluate the contributions of the two non-canonical CRAF pS338 pathways on pancreatic cancer cell survival (via ASK1) and cell proliferation (via Plk1) as these relate to tumor growth and metastasis of pancreatic cancer in vivo. Since mitosis is the most radiosensitive stage of the cell cycle, the goal of Aim 3 is to use mouse models of pancreatic cancer and metastasis to understand how to optimally combine ionizing radiation with blockade of this novel CRAF pS338 pathway which induces mitotic arrest. We anticipate that our innovative approach to target tumor cell survival, proliferation, and radiosensitivity via the K-RAS/CRAF pathway will lead to exciting new opportunities for metastatic pancreatic cancer.

项目摘要/摘要 激活K-RAS突变发生在> 95％的晚期胰腺癌患者中，最近的研究 将CRAF识别为致癌K-RAS下游肿瘤发生所需的激酶。虽然Craf 激酶活性传统上与通过MAPK信号激活肿瘤进展有关，我们已经聚焦了 我们对两种独立于CRAF催化活性和 MAPK的激活。几年前，我们确定了丝氨酸338（PS338）上的CRAF磷酸化 驱动Craf易位到线粒体，并在其中形成复合物并灭活促凋亡 激酶Ask1促进细胞存活。在自然医学新闻界的新手稿中，我们现在报告 CRAF PS338还与细胞周期激酶PLK1在有丝分裂主轴上形成一个复合物，以影响细胞周期 进展。因此，这种丝氨酸对CRAF的遗传或变构抑制均驱动凋亡和 与MAPK途径无关的有丝分裂停滞，而没有观察到MAPK信号传导的抑制剂。 因此，我们的总体目标是靶向CRAF功能并利用其在细胞存活和有丝分裂中的作用 进展，以开发胰腺癌患者的新型治疗方法。提议 研究将定义CRAF的这两个独特的MAPK独特功能如何促进进展和 由致癌K-Ras驱动的胰腺癌转移。在AIM 1中，我们通过 在胰腺癌的独特遗传环境中，非经典CRAF PS338途径被激活。 具体而言，我们将重点介绍K-RAS和PAK如何调节CRAF PS338，因为这些分子是 已知在胰腺癌中失调。目标2的目标是评估两者的贡献 胰腺癌细胞存活（通过Ask1）和细胞增殖（通过 PLK1）由于这些与体内胰腺癌的肿瘤生长和转移有关。由于有丝分裂是最大的 细胞周期的放射敏感阶段，目标3的目标是使用胰腺癌的小鼠模型和 转移了解如何最佳地将电离辐射与这种新型Craf PS338的阻滞结合在一起 诱导有丝分裂停滞的途径。我们预计我们的靶向肿瘤细胞存活的创新方法， 通过K-RAS/CRAF途径的扩散和放射敏感性将为令人兴奋的新机会 转移性胰腺癌。