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.

项目概要虽然多种黑色素瘤疗法已被批准，但 NRAS 突变 (NRASmut) 肿瘤的治疗选择有限，这种肿瘤约占所有黑色素瘤的 30%。 NRASmut 肿瘤极具侵袭性，与患者生存率低相关。这些类型的肿瘤对现有的靶向治疗具有高度耐药性，并且对免疫疗法反应较差。因此，迫切需要确定新的靶点和有效的疗法来帮助对目前可用的治疗没有反应的大量黑色素瘤患者。我们的目标是确定可针对抵消 NRAS 突变黑色素瘤耐药性的关键漏洞。致癌 NRAS 激活 MAPK 和 PI3K 通路。然而，单独抑制任一途径对患者几乎无效，并且共同靶向这两种途径会导致患者出现不可接受的毒性。我们之前报道过，对 BRAF 和 MEK 抑制剂 (MAPKi-R) 耐药的 BRAF 突变型黑色素瘤能够持续激活核糖体蛋白 S6 激酶。我们现在发现 MAPKi-R NRASmut 黑色素瘤依赖 S6K2 同工型生存。在活性 S6K1 的背景下，选择性 S6K2 阻断会扰乱氧化还原和脂质代谢，在对 MAPK 抑制具有抵抗力的 NRASmut 黑色素瘤细胞中引发致命的脂质过氧化。根据我们的初步发现，我们假设 S6K2 控制代谢和氧化还原稳态以及黑色素瘤细胞的存活，从而构成一个新颖且有前途的治疗靶点。由于 S6K 是 MAPK 和 PI3K/mTOR 途径的汇聚节点，我们进一步假设选择性阻断 S6K2 可以克服依赖这些途径的广泛分子机制介导的对 MAPKi 的耐药性。在这个项目中，我们将定义 S6K2 依赖性脂质和氧化还原稳态有助于耐药性并促进 MAPKi-R 黑色素瘤存活的机制。此外，我们将利用黑色素瘤对 S6K2 的依赖性来抵消 MAPKi 耐药性。我们提出的策略与 MAPK/PI3K 抑制显着不同，它将通过靶向代表肿瘤细胞中选择性脆弱性的收敛子网络来实现功能精确性。我们预计我们的研究将提供一个机制框架，为设计直接针对 S6K2 或 S6K2 特异性效应通路的治疗策略提供信息，并改善 NRASmut 黑色素瘤患者和可能的其他类型 RAS 突变肿瘤的治疗结果。