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.

项目总结 虽然已经批准了几种治疗黑色素瘤的方法，但对NRAS突变(NRASmut)肿瘤的治疗选择有限，约占所有黑色素瘤的30%。NRASmut肿瘤侵袭性极强，患者存活率低。这些类型的肿瘤对可用的靶向治疗具有高度抵抗力，对免疫治疗的反应较差。因此，迫切需要确定新的靶点和有效的治疗方法，以帮助对目前可用的治疗无效的大量黑色素瘤患者。我们的目标是确定关键的脆弱性，可以有针对性地抵消NRAS突变黑色素瘤的耐药性。 致癌的NRAS同时激活MAPK和PI3K通路。然而，单独抑制任何一条途径对患者几乎没有效果，共同靶向这两条途径会导致患者不可接受的毒性。我们以前报道过，耐BRAF和MEK抑制剂(MAPKi-R)的BRAF突变型黑色素瘤持续激活核糖体蛋白S6激酶。我们现在发现MAPKi-R NRASmut黑色素瘤依靠S6K2亚型生存。选择性的S6K2阻断，在活性S6K1的背景下，扰乱氧化还原和脂质代谢，在抵抗MAPK抑制的NRASmut黑色素瘤细胞中触发致命的脂质过氧化。根据我们的初步发现，我们推测S6K2控制代谢和氧化还原动态平衡，以及黑色素瘤细胞的存活，从而构成一个新的和有希望的治疗靶点。由于S6K是MAPK和PI3K/mTOR通路的汇聚点，我们进一步推测选择性阻断S6K2可以克服依赖这些通路的广泛分子机制介导的对MAPKi的耐药性。在这个项目中，我们将确定S6K2依赖的脂质和氧化还原动态平衡有助于耐药和促进MAPKi-R黑色素瘤生存的机制。此外，我们将利用黑色素瘤对S6K2的依赖来抵消MAPKi的耐药性。我们提出的策略，与MAPK/PI3K抑制显著不同，将通过选择性地靶向代表肿瘤细胞中的易损性的聚合子网络来实现功能精确度。我们预计，我们的研究将提供一个机制框架，为直接针对S6K2或替代针对S6K2特异性效应通路的治疗策略的设计提供信息，并改善NRASmut黑色素瘤患者和可能的其他类型的RAS突变肿瘤的预后。