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

迫切需要提名可能预测放射治疗和治疗效果的生物标志物。 加速他们的临床翻译。到目前为止，努力一直有限，很大程度上是因为基因特征 调节肿瘤细胞存活及其在单个癌症类型之间和内部的频率还没有研究过 大规模地。我们小组完成了对癌细胞系辐射后存活情况的最大规模的研究， 包括来自26种癌症类型的533个带有基因注释的肿瘤细胞系的多样化集合。至 作为对这项工作的补充，我们最近启动了对&gt；1000基因变异的系统分析，这些变异可以 可能有助于癌细胞对辐射的抵抗力。我们综合了我们的分析工作的结果 以确定预测肺癌细胞对辐射的抵抗力的特征。这项调查的目的是 是为了促进肺癌中两个最重要的辐射抵抗调节因子的临床翻译， NRF2和BRAF。约28%的非小细胞肺癌患者中Nrf2途径发生了基因改变 (NSCLC)和具有NFE2L2或Keap1突变的细胞与抗药性高度相关 辐射。为了确定NRF2活性肿瘤的遗传相关性，我们使用了计算和实验 证明Nrf2和磷脂酰肌醇3-激酶(PI3K)频繁共存的方法 非小细胞肺癌的改变。利用遗传和化学手段，我们证明了拮抗细胞的催化亚单位 PI3K，p110(由PIK3CA编码)，降低NRF2活性，逆转由此驱动的辐射抗性 路径。这些结果为提高Nrf2活性患者的放射增敏策略提供了理论依据 NSCLC通过靶向PI3K。我们的侧写工作也证明了BRAF的关键作用，它是遗传的 在~7%的非小细胞肺癌患者中，肺癌细胞对辐射的抵抗力发生了变化。我们第一次展示了 时间，BRAF激酶结构域突变赋予肺癌对辐射的抵抗力，它们不同于 NRF2途径改变，几乎总是肿瘤的一个次要组成部分(即它们是亚克隆的)。我们用 数学和实验模型表明克隆体系结构对 对靶向治疗和辐射有反应的可能性。总而言之，这些结果提供了一个令人信服的理由 目的：研究Nrf2和BRAF在预测放射治疗后预后中的作用。 这些肿瘤患者的基因组引导放射增敏策略。如果这些假设是正确的， 我们的结果将证明，放射治疗增敏剂可以根据身份和类型进行选择 (克隆性的，亚克隆性的)在病人的癌症中发现的基因改变，促使使用 从一般的方法到由个体肿瘤的基因组成指导的方法的辐射。

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.