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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要超过 40% 的人类癌症是由过度激活的 RTK/RAS/RAF/MEK/ERK 信号 (MAPK 途径）。使用小分子 RAF 或 MEK 抑制剂靶向 MAPK 信号传导是一种经过验证的治疗方法癌症策略，但这些药物的抗肿瘤活性通常会因各种机制而减弱适应性抵抗。其中一种常见机制是负反馈缓解的结果，它促进了上调多种受体酪氨酸激酶 (RTK) 的表达和活性，进而激活存在抑制剂时的 RAS 和下游 MAPK 信号传导。此外，与 MAPK 如何相关的问题定向疗法可以通过对正常组织的影响最小化来达到更高的治疗指数，如何才能做到这一点？它们与免疫检查点疗法的最佳结合在很大程度上仍未解决。 SHP2 (PTPN11) 是非受体蛋白酪氨酸磷酸酶通过介导多个 RTK 下游的信号转导与 GRB2 和其他衔接蛋白结合形成促进 RAS 激活的复合物。 SHP2 有也被认为具有免疫抑制作用，但 SHP2 的这一功能也相对较少待研究。近期开发的有效且选择性的变构小分子抑制剂 SHP2 通过共同靶向两种致癌基因，提供了潜在克服适应性耐药性的机会肿瘤中信号传导和反馈诱导的 RTK 介导的 RAS 激活依赖于失调的 MAPK 发信号。使用这样一种 SHP2 抑制剂 SHP099，我们发现 SHP2 和 MAPK 的组合靶向信号传导阻止了 MAPK 依赖性肿瘤的特定亚群中的适应性耐药。在每个 MAPK 驱动的肿瘤分析，响应 MAPK 诱导 p(Y542)SHP2（SHP2 激活的替代标记物）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针对性治疗方案的侵袭性癌症类型，包括三阴性乳腺癌 (TNBC) 模型，以及 G12 具有 RAS 突变的肿瘤。在相比之下，RAS（G13D）/（Q61X）突变与肿瘤对组合的耐药性相关，揭示了迄今为止尚未认识到突变 RAS 信号传导的复杂性以及不同 RAS 依赖性的变异性上游 RTK/SHP2 信号传导突变体。最后，使用体外共培养肿瘤细胞/T细胞系统，我们发现 SHP2 抑制可增强 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以及生化和基于细胞的方法来全面研究调节野生动物的机制 RTK/SHP2 信号下游的类型和突变 RAS 活性。我们将进一步研究离体和体内体内对 SHP2 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疗法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颖的针对 MAPK 驱动的癌症的有效组合药理学策略。