Mechanistic Insights into ALK Fusion Biology Through Investigation of the Fusion Partner

通过对融合伙伴的调查，深入了解 ALK 融合生物学的机制

• 批准号: 9256883
• 负责人: Merrida Childress
• 金额: $ 2.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256883
• 关键词: Address; Affect; Alpha Cell; Biological Assay; Biology; Biopsy Specimen; CRISPR/Cas technology; Cancer Patient; Cell Line; Cell physiology; Cellular Assay; Cellular Morphology; Characteristics; Chimeric Proteins; Clinical; Computer Simulation; Data; Decision Making; Disease; Effectiveness; Epidermal Growth Factor Receptor; Epithelial; Exhibits; Gene Expression; Gene Rearrangement; Genes; Genetic Engineering; Growth; Hematologic Neoplasms; Hematopoietic; In Vitro; Inflammatory Pseudotumor; Interleukin-3; Investigation; Kinetics; Malignant Neoplasms; Mesenchymal; Migration Assay; Modeling; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Prevalence; Process; Property; Protein Tyrosine Kinase; Proteins; Reporting; Research; Resistance; Role; Sampling; Signal Pathway; Solid Neoplasm; Technology; Testing; Therapeutic; Treatment Efficacy; Tyrosine Kinase Inhibitor; Variant; anaplastic lymphoma kinase; cancer therapy; clinical diagnostics; clinically relevant; crizotinib; disease phenotype; drug efficacy; experimental study; in vitro Assay; in vivo Model; insight; leukemia; mutant; next generation sequencing; relating to nervous system; resistance mechanism; response; retinoic acid receptor alpha; targeted cancer therapy; targeted treatment; therapeutic target; therapy resistant; tumor; tumor growth

ABSTRACT Gene rearrangements involving the anaplastic lymphoma kinase (ALK) represent a unique class of therapeutically targetable oncogenes that are increasingly being detected in numerous epithelial, mesenchymal, hematopoietic, and neural malignancies1. Importantly, ALK fusions have been identified in up to 8% of non-small cell lung cancer (NSCLC) and 50% of inflammatory myofibroblastic tumor (IMT)2,3. The prevalence of ALK fusions highlights the importance of understanding fusion kinase biology in order to develop the most effective therapeutic strategies. While the oncogenic fusion proteins resulting from ALK translocations are valid targets for cancer therapy, our understanding of how to most effectively target these fusions is lacking in comparison to other oncogenic drivers. For example, in EGFR-mutant NSCLC, different EGFR alterations confer varying degrees of sensitivity or resistance to EGFR directed therapies4-8. In addition, for other oncogenic fusions, such as the retinoic acid receptor alpha (RARα) fusions found in subtypes of leukemia, it is known that the particular gene fused to RARα not only affects response to therapy but also can be a therapeutic target itself8. Although many different 5' partner genes have been reported for ALK fusions, treatment of ALK fusion positive cancers is decided without regard to which 5' partner is present. For example, in NSCLC, patients with EML4-ALK, KIF5B-ALK, or TFG-ALK fusions are all treated with the ALK tyrosine kinase inhibitor (TKI), crizotinib. Clinically, ALK TKIs are effective for ALK fusion positive tumors; however, there is little data to address the question of how a different fusion partner may affect pretreatment clinical characteristics, disease responsiveness to targeted therapies, or acquired resistance. Additionally, the role of each 5' partner has not been systematically investigated. Overall, we hypothesize that the 5' partner influences the intrinsic properties of the ALK fusion protein as well as the cellular functions that impact overall oncogenic potential, resulting in variability in disease phenotypes and response to targeted therapies. To test our hypothesis, we will carry out experiments using known ALK fusions detected in NSCLC and IMT to: 1) determine if the 5' partner alters kinase activity and efficacy of ALK TKIs, and 2) determine if the 5' partner of ALK fusions affects oncogenic cellular functions and explore mechanisms that may confer differential oncogenicity. Since more sophisticated next-generation sequencing technologies are coming to the forefront of clinical diagnostics, clinicians will not only know that a tyrosine kinase fusion is present, but also to which specific 5' partner the kinase is fused. Therefore, the findings from these studies are expected to refine the treatment of ALK fusion positive cancers in order to more effectively inhibit tumor growth and understand potential therapeutic resistance mechanisms. Furthermore, as kinase fusions are found in numerous malignancies, these studies may also have potential implications for other kinase-driven cancers.

摘要