REGULATION AND ADAPTIVE MECHANISMS OF ONCOGENIC RAS/ERK SIGNALING

致癌 RAS/ERK 信号传导的调控和适应性机制

• 批准号: 10160858
• 负责人: Poulikos I Poulikakos
• 金额: $ 41.73万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10160858
• 关键词: Accounting; Adaptor Signaling Protein; Affect; Attenuated; BRAF gene; Biochemical; Breast Cancer Model; Cancer Patient; Cell Line; Cell physiology; Cells; Cessation of life; Clinical; Clinical effectiveness; Coculture Techniques; Combined Modality Therapy; Complex; Data; Dependence; Development; Effectiveness; FGFR1 gene; Feedback; Fibroblast Growth Factor Receptors; Goals; Human; Immune; Immune response; Immune system; Immunotherapy; In Vitro; Knowledge; MAP Kinase Gene; MEKs; Malignant Neoplasms; Mediating; Methods; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular; Mutation; Normal Cell; Normal tissue morphology; Oncogenic; Outcome; PI3K/AKT; PTPN11 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proto-Oncogene Proteins c-akt; RAS inhibition; Ras/Raf; Receptor Protein-Tyrosine Kinases; Regulation; Research Personnel; Resistance; Role; Signal Transduction; Surrogate Markers; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Index; Tumor Tissue; Up-Regulation; Xenograft Model; base; cancer type; cell killing; checkpoint therapy; combinatorial; design; effective therapy; engineered T cells; experimental study; follow-up; growth factor receptor-bound protein 2; improved; in vivo; inhibitor/antagonist; insight; melanoma; mutant; neoplastic cell; new technology; novel; patient derived xenograft model; potential biomarker; pre-clinical; predictive marker; prevent; response; small molecule; small molecule inhibitor; targeted treatment; treatment response; triple-negative invasive breast carcinoma; tumor

Project Summary/Abstract Over 40% of human cancers are driven by hyperactivated RTK/RAS/RAF/MEK/ERK signaling (MAPK pathway). Targeting MAPK signaling using small-molecule RAF or MEK inhibitors is a validated therapeutic strategy in cancer, but the antitumor activity of these drugs is commonly attenuated by various mechanisms of adaptive resistance. One such common mechanism is the result of relief of negative feedback which promotes upregulation of expression and activity of multiple Receptor Tyrosine Kinases (RTKs), which in turn activate RAS and downstream MAPK signaling in the presence of inhibitor. Further, questions relating with how MAPK- directed therapies can achieve a higher therapeutic index by minimally affecting normal tissue and how can they be optimally combined with immune checkpoint therapies remain largely unresolved. SHP2 (PTPN11) is a non-receptor protein tyrosine phosphatase that mediates signal transduction downstream of multiple RTKs by associating with GRB2 and other adaptor proteins to form a complex that promotes RAS activation. SHP2 has also been suggested to have an immunosuppressive role, but this function of SHP2 has also been relatively understudied. The recent development of potent and selective allosteric small-molecule inhibitors targeting SHP2 provided the opportunity to potentially overcome adaptive resistance by co-targeting both oncogenic signaling and feedback-induced RTK-mediated RAS activation in tumors dependent on deregulated MAPK signaling. Using one such SHP2 inhibitor, SHP099, we found that combinatorial targeting of SHP2 and MAPK signaling prevented adaptive resistance in defined subsets of MAPK-dependent tumors. In each MAPK-driven tumor analyzed, induction of p(Y542)SHP2, a surrogate marker of SHP2 activation, in response to MAPK inhibition was required for combined treatment sensitivity. The strategy was broadly effective in tumor models representing aggressive cancer types for which there are no targeted therapeutic options currently available, including Triple Negative Breast Cancer (TNBC) models, as well as tumors with RAS mutations at G12. In contrast, RAS(G13D)/(Q61X) mutations were associated with tumor resistance to the combination, revealing a hitherto unappreciated complexity of mutant-RAS signaling and variability in the dependence of different RAS mutants on upstream RTK/SHP2 signaling. Finally, using an in vitro co-culture tumor cells/T cells system we found that SHP2 inhibition enhances T cell function. Based on these observations, we now plan to use specific inhibitors and biochemical and cell-based methods to comprehensively study mechanisms that regulate wild- type and mutant RAS activity downstream of RTK/SHP2 signaling. We will further investigate ex vivo and in vivo for molecular and tumor type-specific determinants of response to combined SHP2 and MAPK inhibition, that may be used as potential biomarkers and of the effects of these therapies on normal tissue and the immune system. The goal is to use the mechanistic knowledge gained by these studies to develop novel effective combinatorial pharmacologic strategies for MAPK-driven cancers.

项目摘要/摘要 超过40％的人类癌症是由过度活化的RTK/RAS/RAF/MEK/ERK信号驱动的（MAPK 途径）。使用小分子RAF或MEK抑制剂靶向MAPK信号是经过验证的治疗方法 癌症的策略，但是这些药物的抗肿瘤活性通常会因各种机制而减弱 自适应抗性。一种常见的机制是缓解负面反馈的结果 多个受体酪氨酸激酶（RTK）的表达和活性的上调，这反过来激活 在存在抑制剂的情况下，RAS和下游MAPK信号传导。此外，与mapk-有关的问题 定向疗法可以通过最小化正常组织来实现更高的治疗指数，如何才能如何 它们与免疫检查点疗法最佳结合，在很大程度上尚未解决。 SHP2（PTPN11）是 非受体蛋白酪氨酸磷酸酶介导多个RTK下游的信号转导， 与GRB2和其他衔接蛋白相关联，形成促进RAS激活的复合物。 SHP2有 还建议具有免疫抑制作用，但是SHP2的这一功能也相对 研究了。最近的有效和选择性的变构小分子抑制剂的靶向 SHP2提供了通过共同靶向的癌症来克服自适应抗性的机会 信号传导和反馈诱导的RTK介导的肿瘤中的RAS激活取决于失控的MAPK 信号。使用这样的SHP2抑制剂SHP099，我们发现SHP2和MAPK的组合靶向 信号传导可防止在MAPK依赖性肿瘤的定义子集中的适应性抗性。在每个MAPK驱动中 分析的肿瘤，SHP2激活的替代标记P（Y542）SHP2的诱导 需要抑制治疗敏感性。该策略在肿瘤模型中广泛有效 代表目前没有针对性治疗方案的积极癌症类型， 包括三重阴性乳腺癌（TNBC）模型以及G12时具有RAS突变的肿瘤。在 对比，RAS（G13D）/（Q61X）突变与肿瘤对组合的抗性有关，揭示了A 迄今为止，突变体-RAS信号传导的复杂性和不同RA的依赖性的可变性 上游RTK/SHP2信号传导上的突变体。最后，使用体外共培养肿瘤细胞/T细胞系统 发现SHP2抑制会增强T细胞功能。基于这些观察，我们现在计划使用特定的 抑制剂和生化和基于细胞的方法，用于全面研究调节野生的机制 RTK/SHP2信号传导下游的类型和突变RAS活性。我们将进一步调查离体和 体内用于响应SHP2和MAPK抑制的反应的分子和肿瘤类型的决定因素， 可以用作潜在的生物标志物以及这些疗法对正常组织和 免疫系统。目的是利用这些研究获得的机械知识来发展新颖 MAPK驱动的癌症的有效组合药理策略。