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: 10591501
• 负责人: Aaron N Hata
• 金额: $ 48.39万
• 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/10591501
• 关键词: Automobile Driving; Biochemical; Biological; Cancer Patient; Cell Survival; 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; 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 Neoplasm; 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 resistance 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; 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.

项目概要/摘要： 抑制致癌激酶如EGFR、ALK、ROS 1（TKI）的靶向治疗已显著改善 肺癌患者的存活率，这些患者的肿瘤在这些基因中具有激活的基因组改变。 不幸的是，这些疗法不是治愈性的，并且患者最终发展出耐药性，导致 疾病进展。我们小组和其他人最近的工作表明， 获得性耐药性可以从最初在药物治疗中存活的残余耐药细胞进化而来， 然后随后在治疗期间获得基因组改变。这表明， 可以改变残余肿瘤细胞的存活和进化，可能会预先阻止耐药克隆的出现。在 使用EGFR突变体和ALK融合肺癌的临床前模型进行的初步研究，我们观察到 在初始TKI治疗中存活的癌细胞表现出APOBEC 3A的表达和活性增加， 胞苷脱氨酶此外，来自EGFR和ALK肺癌患者的临床肿瘤样品的分析 显示在序贯TKI治疗期间APOBEC突变的累积。我们假设APOBEC 3A- 由TKI处理诱导的介导的DNA和RNA编辑促进了药物耐受性克隆的出现， 在治疗过程中肺肿瘤，并促进获得性耐药性的演变。在这个项目中，我们将 开发新型生化和计算工具来研究EGFR突变体和ALK中的APOBEC 3A突变 融合型非小细胞肺癌实验模型和临床肿瘤标本。这些研究将建立 TKI处理和诱导APOBEC诱变之间的因果关系。接下来，我们将调查 响应于基因组不稳定性和/或RNA表达的先天免疫信号传导途径的激活 重复元件是TKI诱导的APOBEC 3A诱变所必需和充分的。最后，我们将确定 APOBEC 3A的诱导是否促进药物耐受性克隆的存活和随后的 获得性耐药性这些研究将产生关于TKI耐药性如何演变的基本生物学见解 在癌基因成瘾的癌症中，并确定新的弱点，可以针对延迟或防止耐药性 发展。