Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.
Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.
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DOI：
10.1038/nm.4040
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发表时间：
2016-03
期刊：
影响因子：
82.9
通讯作者：
Engelman JA
中科院分区：
文献类型：
--
作者：
Hata AN;Niederst MJ;Archibald HL;Gomez-Caraballo M;Siddiqui FM;Mulvey HE;Maruvka YE;Ji F;Bhang HE;Krishnamurthy Radhakrishna V;Siravegna G;Hu H;Raoof S;Lockerman E;Kalsy A;Lee D;Keating CL;Ruddy DA;Damon LJ;Crystal AS;Costa C;Piotrowska Z;Bardelli A;Iafrate AJ;Sadreyev RI;Stegmeier F;Getz G;Sequist LV;Faber AC;Engelman JA
尽管EGFR突变型非小细胞肺癌对EGFR抑制剂的获得性耐药机制已被确定，但对耐药克隆在药物治疗期间如何演变知之甚少。在这里，我们观察到由T790 M看门突变引起的获得性耐药性可以通过选择预先存在的T790 M克隆或通过最初T790 M阴性耐药细胞的遗传进化而发生。耐药途径影响了耐药克隆的生物学，因为从耐药细胞进化而来的那些细胞对靶向T790 M EGFR的第三代EGFR抑制剂的凋亡反应减弱;用navitoclax（BCL-XL和BCL-2的抑制剂）治疗恢复了敏感性。我们使用直接来自EGFR耐药患者肿瘤的培养物证实了这些发现。这些发现提供了证据，证明临床相关的耐药癌细胞既可以预先存在，也可以从耐药细胞进化而来，并指出了在临床上预防或克服耐药性的治疗机会。
Although mechanisms of acquired resistance of EGFR mutant non-small cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here, we observe that acquired resistance caused by the T790M gatekeeper mutation can occur either by selection of pre-existing T790M clones or via genetic evolution of initially T790M-negative drug tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug tolerant cells had a diminished apoptotic response to third generation EGFR inhibitors that target T790M EGFR; treatment with navitoclax, an inhibitor of BCL-XL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug resistant cancer cells can both pre-exist and evolve from drug tolerant cells, and point to therapeutic opportunities to prevent or overcome resistance in the clinic.