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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

基本信息

批准号：
8495296
负责人：
DAVID A CHERESH
金额：
$ 30.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495296
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 response standard care success therapeutic target therapy resistant tumor growth tumor progression tumorigenesis

项目摘要

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.

项目总结/文摘