Mechanisms driving lung cancer evolution during targeted kinase inhibitor treatment

靶向激酶抑制剂治疗期间驱动肺癌演变的机制

• 批准号: 10377999
• 负责人: Aaron N Hata
• 金额: $ 52.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377999
• 关键词: Automobile Driving; Biochemical; Biological; Cancer Patient; Cells; Characteristics; Clinical; Computing Methodologies; Cytidine; Cytidine Deaminase; DNA; DNA Sequence Alteration; Data; Deamination; Development; Disease Progression; Drug Tolerance; Drug resistance; Effectiveness; Elements; Enzymes; Epidermal Growth Factor Receptor; Evolution; Exhibits; Experimental Models; Foundations; Future; Gatekeeping; Genes; Genetic Transcription; Genomic Instability; Genomics; Germ Cells; Goals; Immune; Immune signaling; Innate Immune Response; Lead; Link; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mutagenesis; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Patients; Pharmacotherapy; Phosphotransferases; Play; Pre-Clinical Model; Prevalence; Process; RNA; RNA Editing; ROS1 gene; Residual Tumors; Residual state; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; Virus; Work; acquired drug resistance; biochemical tools; cancer cell; cancer type; clinically relevant; computerized tools; drug development; improved; ineffective therapies; insight; kinase inhibitor; mutant; neoplastic cell; next generation; non-genomic; novel; preempt; prevent; resistance mechanism; response; targeted cancer therapy; targeted treatment; therapeutic development; therapy development; treatment strategy; tumor; tumor heterogeneity

Project Summary/Abstract: Targeted therapies that inhibit oncogenic kinases such as EGFR, ALK, ROS1 (TKIs) have significantly improved the survival of lung cancer patients whose tumors harbor activating genomic alterations in these genes. Unfortunately, these therapies are not curative and patients eventually develop drug resistance leading to disease progression. Recent work by our group and others has demonstrated that genomic mechanisms of acquired drug resistance can evolve from residual drug-tolerant cells that that initial survive drug treatment and then subsequently acquire the genomic alteration during therapy. This suggests that treatment strategies that can alter the survival and evolution of residual tumor cells may pre-empt the emergence of resistant clones. In preliminary studies using preclinical models of EGFR mutant and ALK fusion lung cancer, we have observed that cancer cells surviving initial TKI treatment exhibit increased expression and activity of the APOBEC3A cytidine deaminase. Additionally, analysis of clinical tumor samples from EGFR and ALK lung cancer patients revealed accumulation of APOBEC mutations during sequential TKI therapy. We hypothesize that APOBEC3A- mediated DNA and RNA editing induced by TKI treatment facilitates the emergence of drug tolerant clones in lung tumors during treatment and facilitates the evolution of acquired drug resistance. In this project, we will develop novel biochemical and computational tools to study APOBEC3A mutagenesis in EGFR mutant and ALK fusion non-small cell lung cancer experimental models and clinical tumor specimens. These studies will establish a causal link between TKI treatment and induction of APOBEC mutagenesis. Next, we will investigate whether activation of innate immune signaling pathways in response to genomic instability and/or expression of RNA repeat elements is necessary and sufficient for TKI-induced APOBEC3A mutagenesis. Finally, we will determine whether induction of APOBEC3A promotes the survival of drug tolerant clones and subsequent development of acquired drug resistance. These studies will yield fundamental biological insights into how TKI resistance evolves in oncogene-addicted cancers and identify new vulnerabilities that can be targeted to delay or prevent resistance from developing.

项目摘要/摘要： 抑制诸如EGFR，ALK，ROS1（TKI）等致癌激酶的靶向疗法已显着改善 肺癌患者的存活率在这些基因中激活基因组改变。 不幸的是，这些疗法无法治愈，患者最终会产生耐药性，导致 疾病进展。我们小组和其他人的最新工作表明，基因组机制 获得的耐药性可以从最初生存的药物治疗和 然后随后在治疗过程中获得基因组改变。这表明治疗策略 可以改变残留肿瘤细胞的存活率和演变可能会避开抗性克隆的出现。在 使用EGFR突变体和ALK融合肺癌的临床前模型的初步研究，我们已经观察到 生存初始TKI治疗的癌细胞表现出apobec3a的表达和活性增加 胞苷脱氨酶。此外，分析来自EGFR和ALK肺癌患者的临床肿瘤样本 揭示了顺序TKI治疗过程中APOBEC突变的积累。我们假设apobec3a-- TKI处理引起的介导的DNA和RNA编辑促进了药物耐受克隆在 治疗过程中的肺部肿瘤并促进了获得耐药性的演变。在这个项目中，我们将 开发新型的生化和计算工具来研究EGFR突变体中的APOBEC3A诱变 融合非小细胞肺癌实验模型和临床肿瘤标本。这些研究将确定 TKI处理与诱导APOBEC诱变之间的因果关系。接下来，我们将调查是否 响应基因组不稳定性和/或RNA表达的先天免疫信号通路的激活 重复元素对于TKI诱导的APOBEC3A诱变是必需的，并且足够。最后，我们将确定 诱导APOBEC3A是否促进药物耐受克隆的存活以及随后的发展 获得的耐药性。这些研究将对TKI抗性如何发展产生基本的生物学见解 在癌基因癌中的癌症中，并确定可以针对延迟或防止阻力的新漏洞 从发展。