Identification of Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors

间变性淋巴瘤激酶抑制剂耐药机制的鉴定

• 批准号: 8431743
• 负责人: Jeffrey A. Engelman
• 金额: $ 33.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431743
• 关键词: Adenocarcinoma; Affect; Applications Grants; Biological Markers; Biological Models; Biopsy; Bypass; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Cycle Arrest; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chromosomal Rearrangement; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Coupled; DNA Sequence Rearrangement; Data; Defect; Development; Disease; Disease remission; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Future; Gatekeeping; Gefitinib; Gene Expression Profiling; Genotype; Goals; Growth; In Vitro; Institution; Institutional Review Boards; Laboratories; Laboratory Study; Life; Malignant Neoplasms; Malignant Pleural Effusion; Malignant neoplasm of lung; Mediating; Methodology; Methods; Modeling; Molecular; Molecular Target; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Operative Surgical Procedures; Pathway interactions; Patients; Phase I Clinical Trials; Protein Tyrosine Kinase; Protocols documentation; Relapse; Research Infrastructure; Resistance; Resistance development; Sampling; Seminal; Signal Pathway; Specimen; Testing; Therapeutic; Translating; Tyrosine Kinase Inhibitor; United States; Xenograft Model; anaplastic lymphoma kinase; base; cell growth; chemotherapy; clinical infrastructure; clinical remission; clinically relevant; combinatorial; comparative genomic hybridization; design; genome-wide; improved; in vivo; kinase inhibitor; mutant; never smoker; novel; novel therapeutic intervention; repository; resistance mechanism; resistance mutation; response; subcutaneous; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States. Over the last decade, a number of new therapies targeting signaling pathways that control cell growth and survival have been developed. Some of these, particularly tyrosine kinase inhibitors (TKIs), have shown remarkable antitumor activity in select subsets of lung cancer patients. Examples include gefitinib or erlotinib for EGFR- mutant lung cancers and more recently, crizotinib (PF-02341066) for lung cancers harboring chromosomal rearrangements of ALK (anaplastic lymphoma kinase). These therapies often induce marked responses and clinical remissions; however, cancers invariably develop resistance to TKI therapy, usually within one year of treatment. This type of resistance is termed acquired resistance, and it has severely curbed the impact of these new therapies. In this application, we will focus on ALK-positive lung cancers which affect approximately 8,000 people per year in the United States alone. We have previously shown that the lung cancer patients most likely to harbor ALK rearrangements are the young, never smokers with the adenocarcinoma type of NSCLC. In a seminal phase 1 trial led by our institution, crizotinib induced significant responses in close to 60% of ALK-positive patients, and stabilized disease in an additional 30%. Most patients, however, relapse after approximately one year due to acquired resistance, and there are currently no second-line options for these resistant patients other than standard chemotherapy. Here, we propose methods to discover molecular mechanisms underlying acquired resistance to crizotinib. We will generate laboratory models of ALK-positive NSCLC from patients with the disease. Models that are not already resistant will be made resistant in the laboratory using methodology that we previously used to identify clinically validated mechanisms of EGFR TKI resistance. We will systematically assess each model for the presence of resistance mutations within ALK itself, for activation of alternative growth pathways that allow cells to bypass ALK, and for defects in the cell death machinery. We will also take more unbiased approaches like gene expression profiling and comparative genomic hybridization to discover potentially novel mechanisms of resistance. Based on our findings, we will design and test therapeutic strategies to overcome resistance in vivo. We will also confirm that these resistance mechanisms are clinically relevant by evaluating resistant tumor specimens from patients. Taken together, these studies will enable the rational selection of subsequent, or second-line, treatments for patients who relapse on crizotinib based on the identified mechanism of resistance. These basic studies will therefore translate into new therapeutic approaches in the clinic that provide long lasting and meaningful benefit to our patients.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是美国癌症死亡的主要原因。在过去的十年中，已经开发了许多针对控制细胞生长和存活的信号通路的新疗法。其中一些药物，特别是酪氨酸激酶抑制剂（TKI），在选定的肺癌患者亚群中显示出显着的抗肿瘤活性。例子包括用于治疗 EGFR 突变型肺癌的吉非替尼或厄洛替尼，以及最近用于治疗带有 ALK（间变性淋巴瘤激酶）染色体重排的肺癌的克唑替尼 (PF-02341066)。这些疗法通常会引起显着的反应和临床缓解；然而，癌症总是会对 TKI 治疗产生耐药性，通常是在治疗后一年内。这种类型的耐药性被称为获得性耐药性，它严重抑制了这些新疗法的影响。在此应用中，我们将重点关注 ALK 阳性肺癌，仅在美国，这种癌症每年就影响约 8,000 人。我们之前已经表明，最有可能携带 ALK 重排的肺癌患者是患有腺癌类型 NSCLC 的年轻且从不吸烟的患者。在我们机构领导的一项开创性的 1 期试验中，克唑替尼在近 60% 的 ALK 阳性患者中引起显着缓解，并稳定了另外 30% 的疾病。然而，大多数患者由于获得性耐药而在大约一年后复发，目前除了标准化疗之外，这些耐药患者没有二线选择。在这里，我们提出了发现克唑替尼获得性耐药分子机制的方法。我们将从患有 ALK 阳性 NSCLC 的患者身上建立实验室模型。尚未产生耐药性的模型将在实验室中使用我们之前用于确定临床验证的 EGFR TKI 耐药机制的方法来使其具有耐药性。我们将系统地评估每个模型，以确定 ALK 本身是否存在耐药突变、允许细胞绕过 ALK 的替代生长途径的激活以及细胞死亡机制的缺陷。我们还将采取更公正的方法，例如基因表达谱和比较基因组杂交，以发现潜在的新耐药机制。根据我们的发现，我们将设计和测试克服体内耐药性的治疗策略。我们还将通过评估患者的耐药肿瘤标本来确认这些耐药机制具有临床相关性。总而言之，这些研究将能够根据已确定的耐药机制，合理选择克唑替尼复发患者的后续或二线治疗方法。因此，这些基础研究将转化为临床新的治疗方法，为我们的患者提供持久且有意义的益处。