Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma

ALK 重排淋巴瘤对 ALK 抑制剂的耐药机制

• 批准号: 9111860
• 负责人: Roberto Chiarle
• 金额: $ 40.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111860
• 关键词: Amino Acids; Apoptosis; Binding; Biological; Biology; Bypass; CRISPR/Cas technology; Candidate Disease Gene; Cataloging; Catalogs; Cell Line; Cells; Clinical; Clinical Research; Data; Dependency; Development; Dose; Drug resistance; Epidermal Growth Factor Receptor; Future; Gene Amplification; Gene Rearrangement; Generations; Genes; Genetic; Genetic Screening; Genomics; Goals; Growth; Hematologic Neoplasms; Human; IGF1R gene; In Vitro; Inflammatory Pseudotumor; Ki-1 Large-Cell Lymphoma; Knock-out; Libraries; Lymphocyte Biology; Lymphoma; Malignant Neoplasms; Modality; Molecular; Mutate; Mutation; NPM1 gene; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphatidylinositols; Phosphotransferases; Point Mutation; Protein Tyrosine Kinase; Proteomics; Proto-Oncogene Protein c-kit; Receptor Protein-Tyrosine Kinases; Relapse; Resistance; Resistance development; Role; Sampling; Series; Signal Pathway; Signal Transduction; Solid Neoplasm; Staging; T-Cell Activation; T-Cell Lymphoma; T-Lymphocyte; Therapeutic; Time; Tumor Biology; Tyrosine Kinase Domain; Tyrosine Kinase Inhibitor; Up-Regulation; Withdrawal; anaplastic lymphoma kinase; base; cancer therapy; clinical efficacy; exome sequencing; genome editing; genome-wide; in vitro Model; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; mouse model; mutant; neoplastic cell; novel; novel strategies; nucleophosmin; overexpression; phosphoproteomics; preclinical study; public health relevance; relapse patients; resistance mechanism; response; screening; transcriptome sequencing; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): The Anaplastic Lymphoma Kinase (ALK) is a potent driver oncogene for a relevant subset of cancers, including Anaplastic Large Cell Lymphoma (ALCL), Non Small Cell Lung Cancer (NSCLC), Inflammatory Myofibroblastic tumors (IMT) and neuroblastoma. The recent development and FDA approval of first and second-generation ALK tyrosine kinase inhibitors (TKI) has revolutionized the therapeutic opportunities to treat ALK-driven cancers. In NSCLC TKI inhibitor have dramatic clinical efficacy on such tumors, but the effect is lost after a window of time of 8-10 months because of the development of TKI resistance by the tumor cells. Several molecular mechanisms of resistance have been elucidated or proposed for TKI resistant NSCLC, including ALK mutation, amplifications, or by-pass signaling by other tyrosine kinases. The elucidation of the mechanisms of resistance can dictate additional lines of therapies in relapsing patients. In contrast to NSCLC, in ALCL the clinical studies with TKI are at a very early stage and mechanisms of resistance are almost completely unknown. In this project, we aim at generating a comprehensive characterization of the molecular mechanisms that generate resistance to ALK TKI in ALCL. By hypothesis-driven or screening approaches, we will elucidate most of the resistance mechanisms and we will evaluate in pre-clinical studies additional therapeutic strategies that could be specifically used for each mechanism. Specifically, we will generate a comprehensive catalog of ALK mutations that confer resistance to TKI and their sensitivity to different ALK inhibitors. We will validate ad propose therapies for patients that become resistant by ALK amplification or PI3K upregulation. Finally we will use proteomic and genetic screens to discover novel mechanisms of resistance. Thus, our results will provide an experimental guide for the therapeutic management of lymphoma patients that develop resistance to ALK TKI.

 描述(由申请人提供)：间变性淋巴瘤激酶(ALK)是相关癌症亚群的有效驱动癌基因，包括间变性大细胞淋巴瘤(ALCL)、非小细胞肺癌(NSCLC)、炎症性肌纤维母细胞瘤(IMT)和神经母细胞瘤。最近开发和FDA批准的第一代和第二代ALK酪氨酸激酶抑制剂(TKI)已经彻底改变了治疗ALK驱动的癌症的机会。在非小细胞肺癌中，TKI抑制剂对此类肿瘤有显著的临床疗效，但由于肿瘤细胞对TKI产生耐药性，8-10个月后作用消失。对于耐TKI的非小细胞肺癌，已经阐明或提出了几种耐药的分子机制，包括ALK突变、扩增或其他酪氨酸激酶的旁路信号。耐药机制的阐明可以为复发患者提供额外的治疗途径。与非小细胞肺癌相比，ALCL对TKI的临床研究还处于非常早期的阶段，其耐药机制几乎完全未知。在这个项目中，我们的目标是对ALCL对ALK TKI产生抗性的分子机制进行全面的表征。通过假设驱动或筛选的方法，我们将阐明大多数耐药机制，并将在临床前研究中评估可针对每种机制专门使用的额外治疗策略。具体地说，我们将生成一个全面的ALK突变目录，这些突变赋予对TKI的耐药性及其对不同ALK抑制剂的敏感性。我们将对通过ALK扩增或PI3K上调而变得耐药的患者进行验证和建议治疗。最后，我们将使用蛋白质组和基因筛选来发现新的抗药性机制。因此，我们的结果将为对ALK TKI产生抵抗的淋巴瘤患者的治疗提供实验指导。