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Targeting S6K2 to Overcome Drug Resistance in NRAS-mutant Melanoma

靶向 S6K2 克服 NRAS 突变黑色素瘤的耐药性

基本信息

批准号：
10539830
负责人：
Jessie Villanueva
金额：
$ 52.28万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539830
关键词：
BRAF gene Biochemical Genetics Biology Cell Death Cell Line Cell Survival Cell physiology Clustered Regularly Interspaced Short Palindromic Repeats Data Dependence Development Disease Disease Progression Drug resistance Enzymes FRAP1 gene Fostering Genes Goals Homeostasis Immunotherapy Incidence Knock-out Link Lipid Peroxidation Lipids MAP Kinase Gene MEKs Mediating Melanoma Cell Metabolic Metabolic Control Mitogen-Activated Protein Kinase Inhibitor Molecular Molecular Target Mutation Oncogenic Oxidation-Reduction PPAR alpha Pathway interactions Patients Pharmacotherapy Population Prognosis Protein Isoforms Public Health Reactive Oxygen Species Relapse Reporting Research Resistance Ribosomal Protein S6 Kinase Role Signal Transduction Skin Cancer Testing Therapeutic Toxic effect Up-Regulation base cancer therapy cancer type combat design digital effective therapy efficacious treatment experience genetic approach improved improved outcome inhibitor lipid metabolism melanoma metabolic profile mouse model mutant neoplastic cell new therapeutic target novel novel strategies novel therapeutics pre-clinical response targeted treatment therapeutic target therapeutically effective transcriptomics tumor tumor heterogeneity tumor microenvironment

项目摘要

PROJECT SUMMARY While several therapies have been approved for melanoma, there are limited treatment options for NRAS mutant (NRASmut) tumors, which account for ~30% of all melanomas. NRASmut tumors are extremely aggressive and are associated with poor patient survival. These types of tumors are highly resistant to available targeted therapies and are poorly responsive to immunotherapies. Therefore, there is an urgent unmet need to identify novel targets and effective therapies to help this large population of melanoma patients who do not respond to currently available treatments. Our goal is to identify critical vulnerabilities that can be targeted to offset drug resistance in NRAS mutant melanoma. Oncogenic NRAS activates both the MAPK and PI3K pathways. However, inhibiting either pathway alone is barely effective in patients and co-targeting both pathways leads to unacceptable toxicities in patients. We previously reported that BRAF-mutant melanomas resistant to BRAF and MEK inhibitors (MAPKi-R) have sustained activation of the ribosomal protein S6 kinase. We have now discovered that MAPKi-R NRASmut melanomas rely on the S6K2 isoform for survival. Selective S6K2 blockade, in the context of active S6K1, perturbs redox and lipid metabolism, triggering lethal lipid peroxidation in NRASmut melanoma cells that are resistant to MAPK inhibition. Based on our preliminary findings, we postulate that S6K2 controls metabolic and redox homeostasis, and melanoma cell survival, thereby constituting a novel and promising therapeutic target. As S6K is a node of convergence of the MAPK and PI3K/mTOR pathways, we further posit that selectively blocking S6K2 can overcome resistance to MAPKi mediated by broad molecular mechanisms that rely on these pathways. In this project we will define the mechanism whereby S6K2-dependent lipid and redox homeostasis contributes to drug resistance and promotes survival of MAPKi-R melanoma. Furthermore, we will exploit the dependency of melanoma on S6K2 to offset MAPKi resistance. Our proposed strategy, which is significantly different from MAPK/PI3K inhibition, will enable functional precision by targeting a convergent subnetwork representing a vulnerability selectively in tumor cells. We anticipate that our studies will provide a mechanistic framework to inform the design of therapeutic strategies targeting S6K2 directly, or alternatively, S6K2 specific effector pathways and improve the outcomes of NRASmut melanoma patients and possible other types of RAS-mutant tumors.

项目总结