Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance

黑色素瘤转移和耐药性之间的信号重新连接

基本信息

批准号：
8955610
负责人：
Ze'ev A Ronai
金额：
$ 116.3万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-02 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8955610
关键词：
ATF2 gene Autophagocytosis BRAF gene Breast Cancer Patient Cell Death Cellular Stress Response Complement Development Drug resistance Epigenetic Process Exhibits Future Gap Junctions Gene Expression Genetic Glutamine Hypoxia Hypoxia Pathway Immunologic Surveillance Investigation Lesion MAPK8 gene Malignant neoplasm of pancreas Malignant neoplasm of prostate Metabolism Methods Modality Monitor Mutate Mutation Neoplasm Metastasis Nutrient Oncogenic PDPK1 gene Phenotype Phosphotransferases Play RNA Splicing Resistance Role Signal Transduction Stress Stress Response Signaling Tumor Suppressor Proteins base biological adaptation to stress cancer cell endoplasmic reticulum stress gain of function inhibitor/antagonist melanoma neoplastic cell novel novel therapeutics prevent programs public health relevance response therapy resistant transcription factor tumor ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Malignant cells are continuously exposed to extrinsic (hypoxia, limited access to nutrients, immune surveillance) and intrinsic (oncogenic insults) stresses that culminate in activation of the hypoxia and endoplasmic reticulum stress (ERS) response programs. Tumor cell adaptation to these challenges depends on both genetic (acquisition of new mutations) and epigenetic (modulation of gene expression) mechanisms that underlie tumor survival, metastasis, and resistance to therapy; also known as plasticity. Over the past two decades, my lab has focused on understanding the cellular stress response, particularly the contribution of kinases and ubiquitin ligases. Our studies established a number of paradigms in stress adaptation, with demonstrated significance for the development, progression, and drug resistance of both melanoma and prostate cancer. We defined how subcellular localization dictates the oncogenic or tumor suppressor activity of ATF2, and showed that this is regulated by the AGC kinase PKC. Based on this discovery we performed a screen for inhibitors of this transcription factor-ostensibly undruggable targets- based on altered subcellular localization. Our other recent discovery of a spliced form of ATF2 that exhibits a gain-of-function phenotype will enable us to further redefine the function of ATF2 in melanoma. Further, we identified a mechanism of rewired signaling in which ERK impacts JNK with concomitant effects on PDK1, the master regulator of AGC kinases. This led us to demonstrate the key role played by PDK1 in melanoma. Our future studies will continue to investigate how PDK1 and its downstream targets contribute to melanoma metastasis and drug resistance. Our discovery that the ubiquitin ligases Siah1/2 control the hypoxia response revealed their roles in melanoma and the most aggressive forms of prostate cancer. Siah1/2 also control stress response signaling, establishing a mechanism for commitment to cell death under ischemic conditions. This established the basis upon which we will develop and evaluate first-in-class Siah inhibitors for prostate cancer and melanoma metastasis and resistance. We also recently determined that the RNF5 ubiquitin ligase regulates both autophagy and glutamine metabolism and established a new method to stratify breast cancer patients to select therapies. Lastly, the discovery that RNF125 ubiquitin ligase is a key regulator of melanoma resistance to BRAF inhibitors will drive an investigation in pancreatic cancer, a fraction of which carry mutated RNF125. Collectively, our discoveries reveal that the tumor cell response to stress, which underlies their plasticity, involves the cooperation between rewired signaling and genetic lesions. Our proposed studies will establish novel mechanisms underlying tumor plasticity, enabling the development of novel agents for predicting, monitoring, and preventing tumor metastasis and resistance.

描述（由申请人证明）：恶性细胞是连续暴露于外在的E）和内在的（致癌性侮辱）压力，这些压力是在and -oplast and -oplast stugrum stugrams中的最终压力。转移和对塑料的抗性。前列腺，我们定义了亚细胞定位如何决定ATF2的肿瘤抑制作用，我们在发现的情况下执行了基于转录因子的不良靶标的转录因子，基于我们的其他租金，该目标将展示出启用功能型表型的ATF2。我们在M Elanoma中的ATF2功能。 GATE建立了我们我们的依据，我们的我们我们我们的我们我们会开发并评估前列腺癌的抑制剂。将乳腺癌患者分层为SELAP IE的新方法。 RNF125。肿瘤转移和抗性。