A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.
A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.
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DOI：
10.1158/0008-5472.can-11-1340
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发表时间：
2011-09-15
期刊：
影响因子：
11.2
通讯作者：
Jänne PA
中科院分区：
文献类型：
--
作者：
Sasaki T;Koivunen J;Ogino A;Yanagita M;Nikiforow S;Zheng W;Lathan C;Marcoux JP;Du J;Okuda K;Capelletti M;Shimamura T;Ercan D;Stumpfova M;Xiao Y;Weremowicz S;Butaney M;Heon S;Wilner K;Christensen JG;Eck MJ;Wong KK;Lindeman N;Gray NS;Rodig SJ;Jänne PA
间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI），包括克唑替尼，是临床前模型和ALK易位癌症患者的有效治疗药物。然而，它们的功效最终将受到获得性耐药性的发展的限制。在本文中，我们报告了从克唑替尼治疗的非小细胞肺癌（NSCLC）患者和耐药肿瘤（DFCI 076）产生的细胞系以及研究ALK TKI（TAE 684）敏感性H3122细胞系的耐药版本中确定的两种ALK TKI耐药机制。克唑替尼耐药DFCI 076细胞系具有独特的L1152 R ALK继发突变，并且对结构上不相关的ALK TKI TAE 684也具有耐药性。尽管DFCI 076细胞系的存活仍部分依赖于ALK，但它也包含表皮生长因子受体（EGFR）信号传导的同时共激活。相比之下，TAE 684耐药（TR 3）H3122细胞系不含ALK继发突变，但含有EGFR信号传导的共激活。ALK和EGFR的双重抑制是DFCI 076和H3122 TR 3细胞系的最有效治疗策略。我们进一步确定了一个ALK重排初治NSCLC患者亚组（3/50; 6%），该亚组同时存在EGFR激活突变。我们的研究确定了ALK和EGFR介导的旁路信号通路介导的ALK TKI耐药机制。这些机制可以独立发生，也可以发生在同一种癌症中，这表明ALK和EGFR抑制剂联合使用可能是这些NSCLC患者亚群的有效治疗方法。
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from, a crizotinib treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076), and from studying a resistant version of the ALK TKI (TAE684) sensitive H3122 cell line. The crizotinib resistant DFCI076 cell line, harboured a unique L1152R ALK secondary mutation, and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent co-activation of epidermal growth factor receptor (EGFR) signalling. In contrast, the TAE684 resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harboured co-activation of EGFR signalling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naïve NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signalling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.