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: 10381679
• 负责人: Poulikos I Poulikakos
• 金额: $ 40.9万
• 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/10381679
• 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; insight; melanoma; mutant; neoplastic cell; new technology; novel; patient derived xenograft model; potential biomarker; pre-clinical; predictive marker; prevent; rational design; 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.

项目总结/摘要 超过40%的人类癌症是由过度活化的RTK/RAS/RAF/MEK/ERK信号传导（MAPK）驱动的 途径）。使用小分子RAF或MEK抑制剂靶向MAPK信号传导是一种有效的治疗方法 这些药物的抗肿瘤活性通常被各种机制减弱， 适应性抵抗力。一个这样的共同机制是负反馈的救济的结果， 上调多种受体酪氨酸激酶（RTK）的表达和活性，其反过来激活 RAS和下游MAPK信号传导在抑制剂的存在下。此外，有关MAPK- 定向治疗可以通过最小程度地影响正常组织来实现更高的治疗指数， 它们与免疫检查点疗法的最佳组合在很大程度上仍然没有解决。SHP 2（PTPN 11）是一种 一种非受体蛋白酪氨酸磷酸酶，介导多种RTK下游的信号转导， 与GRB 2和其他衔接蛋白结合形成促进RAS激活的复合物。SHP 2有 也被认为具有免疫抑制作用，但SHP 2的这种功能也相对较弱。 替补演员靶向选择性变构小分子抑制剂的研究进展 SHP 2通过共同靶向两种致癌基因，提供了潜在克服适应性抗性的机会。 信号和反馈诱导的RTK介导的依赖于MAPK失调的肿瘤RAS激活 发信号。使用一种这样的SHP 2抑制剂，SHP 099，我们发现SHP 2和MAPK的组合靶向作用， 信号传导阻止了MAPK依赖性肿瘤的特定亚群中的适应性抗性。在每个MAPK驱动的 分析肿瘤，诱导p（Y 542）SHP 2，SHP 2活化的替代标志物，响应MAPK 联合治疗敏感性需要抑制。该策略在肿瘤模型中广泛有效 代表目前没有靶向治疗选择的侵袭性癌症类型， 包括三阴性乳腺癌（TNBC）模型，以及在G12具有RAS突变的肿瘤。在 相比之下，RAS（G13 D）/（Q61 X）突变与肿瘤对联合治疗的耐药性相关，揭示了RAS（G13 D）/（Q61 X）突变与肿瘤对联合治疗的耐药性相关。 迄今为止未被认识到的muscle-RAS信号传导的复杂性和不同RAS依赖性的可变性 上游RTK/SHP 2信号转导的突变体。最后，利用体外肿瘤细胞/T细胞共培养系统， 发现SHP 2抑制增强T细胞功能。根据这些观察，我们现在计划使用特定的 抑制剂和生物化学和细胞为基础的方法，全面研究机制，调节野生型， 型和突变型RAS活性下游的RTK/SHP 2信号。我们将进一步研究体外和体内 体内对SHP 2和MAPK联合抑制反应的分子和肿瘤类型特异性决定因素， 可以用作潜在的生物标志物，以及这些治疗对正常组织和 免疫系统目标是利用这些研究获得的机械知识来开发新的 MAPK-driven癌症的有效组合药理学策略。