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

• 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
• 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

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 虽然几种治疗方法已被批准用于黑色素瘤，但NRAS突变（NRASmut）肿瘤的治疗选择有限，占所有黑色素瘤的约30%。NRASmut肿瘤具有极强的侵袭性，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抗性，并且对免疫治疗反应不良。因此，迫切需要确定新的靶点和有效的治疗方法，以帮助这一庞大的黑色素瘤患者群体，他们对目前可用的治疗没有反应。我们的目标是确定可以靶向抵消NRAS突变型黑色素瘤耐药性的关键漏洞。 致癌性NRAS激活MAPK和PI 3 K途径。然而，单独抑制任一途径在患者中几乎无效，并且共同靶向两种途径导致患者中不可接受的毒性。我们先前报道了BRAF突变型黑色素瘤对BRAF和MEK抑制剂（MAPKi-R）的耐药性持续激活核糖体蛋白S6激酶。我们现在已经发现MAPKi-R NRASmut黑色素瘤依赖于S6 K2亚型生存。在活性S6 K1的背景下，选择性S6 K2阻断扰乱氧化还原和脂质代谢，在对MAPK抑制有抗性的NRASmut黑素瘤细胞中触发致死性脂质过氧化。基于我们的初步发现，我们假设S6 K2控制代谢和氧化还原稳态，以及黑色素瘤细胞的存活，从而构成一个新的和有前途的治疗靶点。由于S6 K是MAPK和PI 3 K/mTOR通路的汇聚节点，我们进一步证实选择性阻断S6 K2可以克服依赖于这些通路的广泛分子机制介导的对MAPK i的抗性。在这个项目中，我们将定义S6 K2依赖性脂质和氧化还原稳态有助于耐药性和促进MAPKi-R黑色素瘤生存的机制。此外，我们将利用黑色素瘤对S6 K2的依赖性来抵消MAPKi抗性。我们提出的策略，这是显着不同的MAPK/PI 3 K抑制，将使功能的精度，通过靶向一个收敛的子网代表一个脆弱性选择性的肿瘤细胞。我们预计，我们的研究将提供一个机制框架，为设计直接靶向S6 K2或替代S6 K2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突变型肿瘤的结局。