Targeted therapies: Evolve and ... surrender!
Targeted therapies: Evolve and ... surrender!
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靶向治疗：进化并……投降！
DOI：
10.1038/nrclinonc.2011.60
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发表时间：
2011
影响因子：
78.8
通讯作者：
M. Villanueva
中科院分区：
文献类型：
--
作者：
M. Villanueva
荧光原位杂交(FISH)。所有耐药标本均保留了原有的EGFR前耐药突变，49%的患者获得了继发突变T790M，5%的患者发生了MET扩增。研究人员还观察到了另一种以前只在体外发现的突变：5%的患者出现了编码PI3激酶亚基之一(PIK3CA)的基因突变。也许更令人惊讶的是，在分析耐药样本的组织学时，发现其中五种肿瘤已经从腺癌演变为更具反应性的亚群--小细胞肺癌。在这五名患者中，有四名患者接受了化疗，其中三名患者的反应良好。肺腺癌从上皮细胞表型向侵袭性更强的间充质表型转变(上皮-间充质转化，EMT)与EGFR-TKI获得性耐药相关。因此，Sequist和他的合作者试图调查这是否可能是那些没有显示经典T790M突变、MET或PIK3CA突变的样本背后的耐药机制。在这七个肿瘤中，有三个在出现耐药时显示了EMT。最后，为了研究治疗过程中肿瘤的演变，研究人员从三名患者身上获得了为期两年的活组织检查。在厄洛替尼治疗8个月后，其中一名患者产生了获得性T790M突变，当停止治疗10个月时，这种突变是检测不到的。在这一点上，再次使用厄洛替尼治疗，患者出现了第二次反应。另一名患者的临床过程非常相似，在几次活检中检测到T790M突变的获得和丢失。这些结果表明，随着药物的持续选择压力，肿瘤的表型和基因特征如何变化，并突出了对肿瘤进行持续评估以确定患者最佳治疗方案的重要性：“我们计划扩大我们的重复活组织检查计划，并将其扩展到其他类型的靶向治疗和其他癌症...我们希望其他团体也会探讨这些问题，治疗肿瘤学家将与他们的病人更详细地讨论在癌症治疗过程中进行重复活组织检查可能带来的好处。
fluorescence in situ hybridization (FISH). All of the resistant samples retained the original pre-resistant mutation in EGFR, 49% of the patients acquired the secondary mutation T790M and 5% of the patients developed amplification of MET. The researchers also observed another mutation that had previously only been identified in vitro: 5% of the patients showed mutations in the gene encoding for one of the subunits of PI3 kinase (PIK3CA). Perhaps more surprising was the finding—when analyzing the histology of the resistant samples—that five of the tumors had evolved from adenocarcinomas to the more responsive subset, SCLC. Of these five patients, four of them underwent chemotherapy to which three patients responded favorably. A transition from an epithelial cell phenotype to a more invasive and aggressive mesenchymal phenotype (epithelial–mesenchymal transition, EMT) has been associated with EGFR-TKI acquired resistance in lung adenocarcinoma. Thus, Sequist and collaborators sought to investigate whether this could be the resistance mechanism behind those samples that did not show the classic T790M mutation, mutations in MET or PIK3CA. Three of these seven tumors, showed EMT at the time when resistance appeared. Finally, to study the evolution of the tumors during the course of the treatment, the researchers obtained biopsies from three patients for a period of 2 years. After 8 months of treatment with erlotinib, one of the patients became resistant by developing an acquired T790M mutation, which was undetectable when the treatment was withdrawn for 10 months. At that point, treatment with erlotinib was reintroduced and the patient had a second response. A second patient had a very similar clinical course with gain and loss of the T790M mutation that was detected in several biopsies.These results show how the phenotypic and genotypic characteristics of tumors change with continued selective pressure from drugs and highlight the importance of continuous assessment of tumors to identify the best treatment options for patients:“we plan to broaden our program of repeat biopsies and expand it to other types of targeted therapy and other cancers... We hope that other groups will also pursue these questions and that treating oncologists will talk to their patients in more detail about the possible benefits of undergoing repeat biopsies during the course of cancer therapy” concludes Sequist.