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.

项目摘要尽管已经批准了几种疗法用于黑色素瘤，但NRAS突变体（NRASMUT）肿瘤的治疗选择有限，占所有黑色素瘤的约30％。 Nrasmut肿瘤非常侵略性，与患者生存不良有关。这些类型的肿瘤对可用的靶向疗法具有高度耐药性，并且对免疫疗法的反应不佳。因此，迫切需要确定新的靶标和有效疗法，以帮助对当前可用治疗的大量黑色素瘤患者。我们的目标是确定可以针对NRAS突变体黑色素瘤中耐药性的关键脆弱性。致癌NRA激活MAPK和PI3K途径。但是，仅抑制任何一种途径在患者中几乎没有有效的效果，并且对这两种途径的共同靶向都会导致患者无法接受的毒性。我们先前报道说，BRAF突变剂黑色素瘤对BRAF和MEK抑制剂（MAPKI-R）具有核糖体蛋白S6激酶的持续激活。现在，我们发现Mapki-r Nrasmut黑色素瘤依赖于S6K2同工型来生存。选择性S6K2阻断，在活性S6K1的背景下，Perturbs氧化还原和脂质代谢，触发了对MAPK抑制作用的Nrasmut黑色素瘤细胞中致命的脂质过氧化。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，从而构成了一个新颖而有希望的治疗靶标。由于S6K是MAPK和PI3K/MTOR途径的收敛性节点，因此我们进一步认为，有选择地阻止S6K2可以克服对依赖这些途径的宽分子机制介导的对MAPKI的抗性。在这个项目中，我们将定义S6K2依赖性脂质和氧化还原稳态的机制，从而有助于耐药性，并促进MAPKI-R黑色素瘤的生存。此外，我们将利用黑色素瘤对S6K2的依赖性来抵消MAPKI抗性。我们提出的策略与MAPK/PI3K抑制显着不同，将通过靶向代表肿瘤细胞中脆弱性的收敛子网来实现功能精度。我们预计我们的研究将提供一个机械框架，以直接或直接靶向S6K2的治疗策略，或者是S6K2特异性效应子途径，并改善NRASMUT黑色素瘤患者和其他可能的RAS突变剂肿瘤的结果。