A biomarker-driven strategy to guide the use of radiotherapy in non-small cell lung cancer

指导非小细胞肺癌放疗使用的生物标志物驱动策略

• 批准号: 9928028
• 负责人: Mohamed E. Abazeed
• 金额: $ 36.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9928028
• 关键词: Accounting; Adoption; Architecture; BRAF gene; Biological Markers; Biopsy Specimen; Cancer Etiology; Cancer Patient; Cancer cell line; Catalogs; Catalytic Domain; Categories; Cell Survival; Cells; Cessation of life; Chemicals; Clinical; Clinical Research; Clinical Trials; Collection; Complement; Data; Dependence; Drug Combinations; Evolution; Experimental Models; Frequencies; Gene Expression; Genetic; Genetic Determinism; Genetic Variation; Geography; Goals; Immunofluorescence Immunologic; Individual; Investigation; Lead; Lung Neoplasms; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methods; Minor; Molecular; Mutation; NF-E2-related factor 2; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; PIK3CA gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphatidylinositols; Phosphotransferases; Proto-Oncogene Proteins B-raf; Radiation; Radiation Tolerance; Radiation therapy; Radiosensitization; Recurrence; Regimen; Research; Resistance; Role; Sampling; Technology; Testing; Therapeutic; Time; Translations; Tumor Cell Line; United States; Variant; Work; actionable mutation; base; biomarker-driven; cancer cell; cancer type; chemoradiation; chemotherapy; clinical translation; clinically actionable; efficacy evaluation; exome sequencing; experimental study; genetic variant; genomic data; in vivo; individual patient; inhibitor/antagonist; innovation; kinase inhibitor; lung cancer cell; mathematical model; mortality; mouse model; neoplastic cell; novel therapeutics; outcome prediction; palliative; patient derived xenograft model; programs; radiation resistance; radiation response; radioresistant; response; standard of care; targeted treatment; tumor; tumor DNA

There is an urgent need to nominate biomarkers that are likely to predict the efficacy of radiotherapy and accelerate their clinical translation. Efforts thus far have been limited in large part because the genetic features regulating tumor cell survival and their frequency across and within individual cancer types had not been studied on a large-scale. Our group completed the largest profiling effort of survival after radiation in cancer cell lines, comprising a diverse collection of 533 genetically annotated tumor cell lines from 26 cancer types. To complement this work, we recently initiated the systematic profiling of >1000 genetic variants that could potentially contribute to the resistance of cancer cells to radiation. We combined results from our profiling efforts to identify features that predict the resistance of lung cancer cells to radiation. The objective in this investigation is to advance the clinical translation of two of the most important regulators of radiation resistance in lung cancer, Nrf2 and Braf. The Nrf2 pathway is genetically altered in ~28% of patients with non-small cell lung cancer (NSCLC) and cells with mutations in NFE2L2 or KEAP1 are the most highly correlated with resistance to radiation. To identify genetic dependencies of Nrf2-active tumors, we used computational and experimental approaches to demonstrate the frequent co-occurrence between Nrf2 and phosphoinositide 3-kinase (PI3K) alteration in NSCLCs. Using genetic and chemical means we show that antagonizing the catalytic subunit of PI3K, p110 (encoded by PIK3CA), decreases Nrf2 activity and reverses radiation resistance driven by this pathway. These results provide the rationale to advance a radiosensitization strategy for patients with Nrf2-active NSCLC by targeting PI3K. Our profiling efforts also demonstrate a critical role for BRAF, which is genetically altered in ~7% of patients with NSCLC, in the resistance of lung cancer cells to radiation. We show, for the first time, that BRAF kinase domain mutations confer resistance to radiation in lung cancers and that they, unlike Nrf2 pathway alterations, are almost invariably a minor component of the tumor (i.e. they are subclonal). We use mathematical and experimental models to show that clonal architecture has significant implications for the likelihood of response to targeted therapies and radiation. Together, these results provide a compelling rationale to examine the role of Nrf2 and Braf alterations in predicting outcomes after radiotherapy and advance a genomically-guided radiosensitization strategy for patients with these tumors. If these hypotheses are correct, our results will demonstrate that radiotherapeutic sensitizers can be selected based on both the identity and type (clonal v. subclonal) of genetic alterations identified in a patient's cancer, prompting an evolution in the use of radiation from a generic approach to one that is guided by the genetic composition of individual tumors.

迫切需要提名可能预测放疗效率和 加速其临床翻译。迄今为止的努力在很大程度上受到限制，因为遗传特征 尚未研究调节肿瘤细胞存活及其在各个癌症类型中的频率 在大规模上。我们的小组完成了癌细胞系辐射后最大的生存概况， 包括从26种癌症类型的533个普遍注释的肿瘤细胞系组成的潜水员集合。到 完成这项工作，我们最近启动了> 1000个遗传变异的系统分析 有可能导致癌细胞对辐射的抗性。我们结合了分析工作的结果 确定可以预测肺癌细胞对辐射的耐药性的特征。这项调查的目的 是为了推动肺癌中两个最重要的辐射耐药性调节剂的临床翻译，即 NRF2和BRAF。在约28％的非小细胞肺癌患者中，NRF2途径通常改变 （NSCLC）和具有NFE2L2或KEAP1突变的细胞与对抗性的高度相关 辐射。为了鉴定NRF2活性肿瘤的遗传依赖性，我们使用了计算和实验性 证明NRF2和磷酸肌醇3-激酶（PI3K）之间经常同时出现的方法 NSCLC的改变。使用遗传和化学方法，我们表明对抗的催化亚基 PI3K，P110（由PIK3CA编码），降低NRF2活性并逆转由此驱动的辐射电阻 路径。这些结果为NRF2活性患者推动了放射敏化策略提供了基本原理 NSCLC通过靶向PI3K。我们的分析工作也表明了BRAF的关键作用，这是一般的 在肺癌细胞对放射线的耐药性中，约7％的NSCLC患者改变了。我们显示，第一个 时间，BRAF激酶结构域突变会议会议对肺癌中辐射的抵抗力，并且它们与 NRF2途径改变几乎是肿瘤的次要组成部分（即它们是亚克隆的）。我们使用 数学和实验模型表明克隆建筑对 对靶向疗法和辐射的反应的可能性。这些结果共同提供了令人信服的理由 检查NRF2和BRAF改变在预测放射治疗后的结局中的作用并提高A 这些肿瘤患者的基因指导放射敏策略。如果这些假设是正确的， 我们的结果将证明可以根据身份和类型选择放射性传感器 （克隆案诉亚克隆）在患者癌症中鉴定出的遗传改变，促使使用的进化 从通用方法到由单个肿瘤的遗传组成指导的辐射。