Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.
Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.
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DOI：
10.1158/2159-8290.cd-15-0399
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发表时间：
2015-07
期刊：
影响因子：
28.2
通讯作者：
Sequist LV
中科院分区：
文献类型：
--
作者：
Piotrowska Z;Niederst MJ;Karlovich CA;Wakelee HA;Neal JW;Mino-Kenudson M;Fulton L;Hata AN;Lockerman EL;Kalsy A;Digumarthy S;Muzikansky A;Raponi M;Garcia AR;Mulvey HE;Parks MK;DiCecca RH;Dias-Santagata D;Iafrate AJ;Shaw AT;Allen AR;Engelman JA;Sequist LV
Rociletinib是一种第三代EGFR抑制剂，在T790M肺癌中具有活性，T790M是大多数第一代EGFR耐药的看门人突变。我们对处于罗西替尼进展期的患者进行了活检，以探索耐药机制。在12例罗西替尼起始t790m阳性癌症患者中，6例有T790野生型罗西替尼耐药活检。2例T790野生型肿瘤发生小细胞肺癌转化；3例t790m阳性肿瘤获得EGFR扩增。我们记录了T790野生型和t790m阳性克隆在单次罗西替尼前活检中共存。事实上，t790m阳性细胞的预处理部分影响了对罗西莱替尼的反应。纵向ctDNA分析显示，在一些患者中，血浆EGFR激活突变和T790M的增加预示着罗西替尼耐药，而在另一些患者中，激活突变增加，但T790M仍被抑制。总之，这些发现表明，当采用针对单一耐药机制的治疗时，肿瘤异质性的作用。为了进一步改善结果，还需要针对T790野生型克隆的联合方案。
Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790 wild-type rociletinib-resistant biopsies. Two T790 wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790 wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. In fact, the pre-treatment fraction of T790M-positive cells impacted response to rociletinib. Longitudinal ctDNA analysis revealed an increase in plasma EGFR activating mutation and T790M heralded rociletinib resistance in some patients, while in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are employed. To further improve outcomes, combination regimens that also target T790 wild-type clones are required.