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2016年3月6日 讯 - - 虽然非小细胞肺癌（NSCLC）表皮生长因子受体（EGFR）的突变对癌细胞对EGFR抑制剂药物产生抗性的机理已经较为明确。但在药物治疗过程中，NSCLC如何获得EGFR突变并发展成对抑制剂产生抗性的机理仍然不清楚。最近来自波士顿哈佛医学院的Jeffrey A Engelman带领他们小组在Nature Medicine杂志上发表一篇文章解释临床治疗中肿瘤如何进化获得EGFR抑制剂抗性。他们实验发现，癌细胞存在两种方式进化成表皮生长因子受体突变T790M而获得对EGFR抑制剂抗性：一种是通过癌细胞预先存在EGFR T790M阳性突变，然后经过药物筛选而获得抗性；另一种是癌细胞最初为EGFR T790M突变为阴性，但存在癌细胞对抑制剂药物耐受，这些细胞通过遗传进化而获得药物抗性。
肿瘤细胞中参与抗抑制剂药物相关的信号通路也会影响癌细胞对其他药物的敏感性。经由药物耐受的癌细胞进化获得对EGFR抑制剂抗性的肿瘤对第三代靶向EGFR T790M突变的抑制剂具有一定的抵抗能力。但如果和靶向抗凋亡因子BCL-xl和BCL-2抑制剂（Nacvitoctax）联用，可以还原其对EGFR抑制剂药物的敏感性。
然后，他们还从对EGFR抑制剂药物具有抗性的癌症患者身上分离培养了肿瘤细胞，在这些癌细胞上重复出同样的实验结果。
最后，这些实验结果解释了临床上出现的耐药/抗药的癌细胞是如何进化得来的：耐药癌细胞既可以是预先存在癌症患者肿瘤中；也可能是在药物治疗过程中，从对药物耐受的癌细胞群进化而来。这些研究结果将有助于研究人员和医生更好的靶向治疗临床中的肿瘤抗性。（生物谷Bioon.com）
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Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition
Aaron N Hata, Matthew J Niederst, Hannah L Archibald, Maria Gomez-Caraballo, Faria M Siddiqui, Hillary E Mulvey, Yosef E Maruvka, Fei Ji, Hyo-eun C Bhang, Viveksagar，Krishnamurthy Radhakrishna, Giulia Siravegna, Haichuan Hu, Sana Raoof, Elizabeth Lockerman, Anuj Kalsy, Dana Lee, Celina L Keating, David A Ruddy, Leah J Damon, Adam S Crystal, Carlotta Costa, Zofia Piotrowska, Alberto Bardelli, Anthony J Iafrate, Ruslan I Sadreyev, Frank Stegmeier, Gad Getz, Lecia V Sequist, Anthony C Faber & Jeffrey A Engelman
Although mechanisms of acquired resistance of epidermal growth factor receptor (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 EGFRT790M gatekeeper mutation can occur either by selection of pre-existing EGFRT790M-positive clones or via genetic evolution of initially EGFRT790M-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 EGFRT790M; treatment with navitoclax, an inhibitor of the anti-apoptotic factors 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 they point to therapeutic opportunities to prevent or overcome resistance in the clinic.
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