A Convergent Node in Melanoma to Block Multiple Oncogenic Pathways Simultaneously

摘要 尽管最近在黑色素瘤的靶向治疗方面取得了重大进展，但几乎普遍的最终结果是， 获得耐药性仍然是阻止患者获得持久疗效的主要障碍， 生存为了解决这一关键的未满足的需求，我们最近使用了患者样本和模型 系统，以确定S6 K1作为一个关键的抗耐药治疗的目标，位于 MAPK、CDK 4/6和PI 3 K途径的下游会聚点。重要的是这些 是黑色素瘤发生和已知BRAF和MEK抑制剂的主要驱动因素 耐药机制，假定S6 K1，一个研究不足的药物靶点，作为一个潜在的广泛使用 补救和/或一线治疗。我们的初步数据与这一假设一致，因为 药理学S6 K1抑制逆转了几种药物和遗传学中MAPK抑制剂的耐药性。 contexts.我们的中心假设是，了解机制基础和临床 S6 K1抑制在黑色素瘤中的适用性将允许改进下一代免疫抑制剂的设计。 S6 K1抑制剂和联合治疗，以及对药物的更深入的功能理解 通过S6 K1和下游的抗性机制运作。具体目标1将重点 将S6 K1开发为耐药性和肿瘤背景下的关键药物靶点 启动，其临床相关性将在一系列临床活检中进行调查。具体 目的2将确定S6 K1下游的致癌机制，重点是 对细胞周期和新陈代谢的影响。总体而言，成功完成本研究将提供 为S6 K1作为一个有前途的广泛使用的治疗靶点提供了证据基础，其机制 进一步完善药理学S6 K抑制剂的未来设计和用途。

ABSTRACT Despite recent major advances in targeted therapy for melanoma, the nearly universal eventual acquisition of drug resistance remains a major hurdle that prevents durable gains in patient survival. To address this critical unmet need, we have recently used patient samples and model systems to identify S6K1 as a critical counter-resistance therapy target that lies at the downstream convergence point of the MAPK, CDK4/6, and PI3K pathways. Importantly, these are the primary drivers of both melanomagenesis and of known BRAF and MEK inhibitor resistance mechanisms, positing S6K1, an understudied drug target, as a potential broad-use salvage and/or frontline therapy. Our preliminary data is consistent with this hypothesis, as pharmacological S6K1 inhibition reversed MAPK inhibitor resistance in several drug and genetic contexts. Our central hypothesis is that understanding the mechanistic basis and clinical applicability of S6K1 inhibition in melanoma will allow for improved design of next-generation S6K1 inhibitors and combination therapies, as well as a deeper functional understanding of drug resistance mechanisms operating through and downstream of S6K1. Specific Aim 1 will focus on developing S6K1 as a key drug target in the contexts of both drug resistance and tumor initiation, and its clinical relevance will be interrogated in a series of clinical biopsies. Specific Aim 2 will determine the oncogenic mechanisms downstream of S6K1, with distinct focuses on its impact on cell cycle and metabolism. Overall, successful completion of this study will provide an evidential basis for S6K1 as a promising broad-use therapeutic target, with a mechanistic underpinning to further refine future designs and uses of pharmacological S6K inhibitors.