New therapeutic opportunities from mining polypharmacology mechanisms of ceritinib in ALK-negative non-small cell lung cancer

挖掘色瑞替尼治疗 ALK 阴性非小细胞肺癌的多药理学机制带来新的治疗机会

• 批准号: 9925185
• 负责人: BRENT KUENZI
• 金额: $ 8.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925185
• 关键词: ALK gene; Award; Bioinformatics; Biological Assay; Biology; Cancer Patient; Cancer cell line; Cell Survival; Chemicals; Chimeric Proteins; Clinical; Combined Modality Therapy; Data Set; Drug Screening; Drug Targeting; Drug usage; Elements; FDA approved; Gene Silencing; Generations; Genetic; Genetic Transcription; Genomics; IGF1R gene; Immunoblotting; Immunofluorescence Immunologic; Immunohistochemistry; Immunoprecipitation; In Vitro; Institutes; Institution; KRAS2 gene; Knowledge; Lead; Letters; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mining; Molecular; Molecular Biology Techniques; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; PTK2 gene; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphotransferases; Proteins; Proteomics; RHOA gene; Regulation; Research; Research Personnel; Resistance; Role; Saint Jude Children' s Research Hospital; Scientist; Signal Transduction; System; Systems Biology; Technology; Testing; Training; Tubulin; Tumor Volume; Work; Xenograft Model; anaplastic lymphoma kinase; anticancer activity; anticancer research; base; biomarker development; cancer cell; career; clinical development; crizotinib; design; driver mutation; drug action; drug candidate; effective therapy; experimental study; in vivo; inhibitor/antagonist; interest; kinase inhibitor; knock-down; medical specialties; mutant; nano-string; novel; novel drug combination; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; patient stratification; patient subsets; phosphoproteomics; pre-doctoral; prevent; programs; resistance gene; synergism

Project Summary While there have been advances in targeting actionable oncogenes such as ALK fusion proteins, the majority of non-small cell lung cancer patients feature either difficult to target mutations, e.g. KRAS, or lack known oncogenic drivers. These patients do not derive much benefit from currently approved therapies. Therefore, in order to find effective treatments for these patients, novel strategies need to be implemented to find therapies that are able to kill lung cancer cells and can be rapidly implemented clinically. Many targeted drugs show potent anticancer activity in subsets of NSCLC, which is often unrelated to inhibition of the cognate targets of these drugs. These beneficial off-targets can be exploited to identify novel drug repurposing opportunities that allow for the treatment of these difficult to treat cancers. Detailed drug profiling is best done using unbiased chemical and systems biology approaches. Chemical proteomic experiments investigate direct drug-protein interactomes giving a number of possible candidate targets. These interactomes can be integrated with global signaling changes measured by phosphoproteomics to give a comprehensive view of the mechanism of action of a drug. Ceritinib is an FDA-approved ALK/IGF1R inhibitor for the treatment of ALK positive non-small cell lung cancer (NSCLC) and we observed that ceritinib has unexpected activity in KRAS mutant NSCLC. A focused chemical proteomic profiling of ceritinib has identified a number of novel targets of ceritinib including FAK1 and RSK1/2. Preliminary studies into ceritinib’s mechanism of action have shown alterations in the cross talk signaling between the KRAS and RHOA pathways. However, the functional relevance and exact molecular mechanisms of such regulation remain unclear. Finally, based on this mechanism we designed a novel drug combination strategy combining ceritinib with the FDA-approved tubulin inhibitor, paclitaxel. We will test the hypothesis that the molecular determinants following inhibition of FAK1 and RSK1/2 by ceritinib carry predictive ability for ceritinib and paclitaxel combination efficacy by achieving the following aims. Aim 2.1: To evaluate the role of YB1 in the observed synergy between ceritinib and paclitaxel. Aim 2.2: To investigate the role of GEF-H1 in ceritinib’s mechanism of action. Aim 2.3: To characterize both ceritinib monotherapy and paclitaxel combination therapy in KRAS-mutant NSCLC PDX models. We will then have a greater understanding of the relevant downstream molecular determinants of ceritinib’s mechanism of action and of the observed synergy with paclitaxel. This will ultimately lead to predictive capabilities for ceritinib sensitivity and further clinical development of ceritinib to treat patients whom will benefit.

项目概要 虽然针对可作用癌基因（例如 ALK 融合蛋白）方面取得了进展，但大多数 的非小细胞肺癌患者具有难以靶向的突变，例如KRAS，或缺乏已知的 致癌驱动因素。这些患者并没有从目前批准的疗法中获得太多益处。因此，在 为了找到这些患者的有效治疗方法，需要实施新的策略来寻找治疗方法 能够杀死肺癌细胞，可以快速应用于临床。多种靶向药物显示 在非小细胞肺癌亚群中具有有效的抗癌活性，这通常与抑制相关靶点无关 这些药物。可以利用这些有益的脱靶来识别新的药物再利用机会， 允许治疗这些难以治疗的癌症。 详细的药物分析最好使用公正的化学和系统生物学方法来完成。化学 蛋白质组学实验研究直接的药物-蛋白质相互作用组，给出了许多可能的候选者 目标。这些相互作用组可以与磷酸蛋白质组学测量的全局信号变化相整合 全面了解药物的作用机制。色瑞替尼是 FDA 批准的 ALK/IGF1R 抑制剂用于治疗 ALK 阳性非小细胞肺癌 (NSCLC)，我们观察到色瑞替尼 在 KRAS 突变 NSCLC 中具有意想不到的活性。色瑞替尼的重点化学蛋白质组学分析 确定了色瑞替尼的许多新靶点，包括 FAK1 和 RSK1/2。色瑞替尼的初步研究 作用机制显示 KRAS 和 RHOA 之间的串扰信号发生改变 途径。然而，这种调节的功能相关性和确切的分子机制仍然存在 不清楚。最后，基于该机制我们设计了一种新的联合色瑞替尼的药物组合策略 与 FDA 批准的微管蛋白抑制剂紫杉醇一起使用。 我们将检验以下假设：色瑞替尼抑制 FAK1 和 RSK1/2 后的分子决定因素 通过实现以下目标，具有对色瑞替尼和紫杉醇联合疗效的预测能力。目标 2.1： 评估 YB1 在色瑞替尼和紫杉醇之间观察到的协同作用中的作用。目标 2.2：调查 GEF-H1 在色瑞替尼作用机制中的作用。目标 2.3：描述色瑞替尼单一疗法和 KRAS 突变 NSCLC PDX 模型中的紫杉醇联合疗法。届时我们将拥有更大的 了解色瑞替尼作用机制的相关下游分子决定因素以及 观察到与紫杉醇的协同作用。这最终将带来色瑞替尼敏感性的预测能力和 色瑞替尼的进一步临床开发以治疗将从中受益的患者。