Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors
Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors
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DOI：
10.1158/0008-5472.can-14-3437
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发表时间：
2015-07-15
期刊：
影响因子：
11.2
通讯作者：
Schatz, Jonathan H.
中科院分区：
文献类型：
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作者：
Amin, Amit Dipak;Rajan, Soumya S.;Schatz, Jonathan H.
间变性淋巴瘤激酶（ALK）在某些癌症亚群中染色体重排，包括2%至7%的非小细胞肺癌（NSCLC）和类似于70%的间变性大细胞淋巴瘤（ALCL）。ALK激酶抑制剂crizotinib和ceritinib被批准用于复发性ALK(+) NSCLC，但获得性耐药限制了这些药物的中位无进展生存期平均为10个月。激酶结构域突变在25% - 37%的耐药NSCLC样本中可检测到，伴随或不伴随ALK突变的旁路信号通路的激活经常被检测到。在这里，我们报道，与非小细胞肺癌细胞相比，耐药ALCL细胞没有通过激活替代信号通路来绕过ALK的证据。相反，在这种情况下选择的耐药性反映了ALK本身的上调。值得注意的是，在不使用克唑替尼或西瑞替尼的情况下，我们发现ALK信号的增加会迅速阻止或杀死细胞，从而通过间断给药而不是连续给药来延长体内耐药肿瘤的控制时间。此外，即使在激酶结构域检测到耐药突变，突变ALK的过表达对肿瘤细胞也是有毒的。我们通过异位表达活化的NPM-ALK融合癌蛋白，将人ALCL细胞转化为细胞因子独立的小鼠前b细胞，证实了这些发现。总之，我们的研究结果显示了ALK活化如何作为肿瘤细胞活力的双刃剑，具有潜在的治疗意义。AACR (C) 2015。
The anaplastic lymphoma kinase (ALK) is chromosomally rearranged in a subset of certain cancers, including 2% to 7% of non-small cell lung cancers (NSCLC) and similar to 70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK(+) NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to similar to 10 months. Kinase domain mutations are detectable in 25% to 37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug-resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications. (C)2015 AACR.