Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer.
Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer.
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DOI：
10.1200/po.17.00263
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发表时间：
2018
影响因子：
4.6
通讯作者：
Sequist LV
中科院分区：
文献类型：
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作者：
Piotrowska Z;Hazar-Rethinam M;Rizzo C;Nadres B;Van Seventer EE;Shahzade HA;Lennes IT;Iafrate AJ;Dias-Santagata D;Leshchiner I;Jessop NA;Hu H;Digumarthy SR;Nagy RJ;Lanman RB;Moody S;Niederst MJ;Engelman JA;Hata AN;Corcoran RB;Sequist LV
第三代表皮生长因子受体（EGFR）抑制剂（如nazartinib）对EGFR突变阳性肺癌具有活性，T790 M介导的对初始抗EGFR治疗的获得性耐药，但一些患者的反应混合。在纳扎替尼治疗之前、期间和之后，从两名患者中获得多个系列肿瘤和液体活检。进行下一代测序和液滴数字聚合酶链反应以评估异质性和克隆动力学。我们观察到T790M依赖性和非依赖性克隆在这两个患者的同时出现。系列血浆液滴数字聚合酶链反应说明了响应于各种全身治疗的相对克隆丰度的变化，证实了观察到的临床混合放射学反应的分子基础。对靶向孤立耐药机制的治疗的异质性反应可以通过具有不同遗传特征的共存肿瘤亚克隆来解释。连续液体活检提供了一个机会，以监测克隆动力学和耐药性的出现，并可能代表一个有用的工具，以指导治疗策略。
Third-generation epidermal growth factor receptor (EGFR) inhibitors like nazartinib are active against EGFR mutation–positive lung cancers with T790M-mediated acquired resistance to initial anti-EGFR treatment, but some patients have mixed responses. Multiple serial tumor and liquid biopsies were obtained from two patients before, during, and after treatment with nazartinib. Next-generation sequencing and droplet digital polymerase chain reaction were performed to assess heterogeneity and clonal dynamics. We observed the simultaneous emergence of T790M-dependent and -independent clones in both patients. Serial plasma droplet digital polymerase chain reaction illustrated shifts in relative clonal abundance in response to various systemic therapies, confirming a molecular basis for the clinical mixed radiographic responses observed. Heterogeneous responses to treatment targeting a solitary resistance mechanism can be explained by coexistent tumor subclones harboring distinct genetic signatures. Serial liquid biopsies offer an opportunity to monitor clonal dynamics and the emergence of resistance and may represent a useful tool to guide therapeutic strategies.