The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
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DOI：
10.1158/2159-8290.cd-13-0846
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发表时间：
2014-06
期刊：
影响因子：
28.2
通讯作者：
Engelman JA
中科院分区：
文献类型：
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作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
携带间变性淋巴瘤激酶（ALK）基因重排的非小细胞肺癌（NSCLC）总是对ALK酪氨酸激酶抑制剂（TKI）克唑替尼产生耐药性。在此，我们报告了在克唑替尼耐药背景下对下一代ALK TKI塞瑞替尼（LDK 378）进行的首次临床前评价。对克唑替尼获得性耐药的体外和体内模型（包括从克唑替尼耐药NSCLC患者活检中建立的细胞系）的研究显示，ceritinib可有效克服克唑替尼耐药突变。特别是，塞瑞替尼可有效抑制携带L1196M、G1269A、I1171T和S1206Y突变的ALK，塞瑞替尼与ALK结合的共晶体为这种增强的效力提供了结构基础。然而，我们观察到塞瑞替尼没有克服两种克唑替尼耐药ALK突变G1202R和F1174C，并且在获得性塞瑞替尼耐药患者的11例活检中有5例发现了其中一种突变。总之，我们的结果表明，塞瑞替尼可以克服克唑替尼耐药，这与临床数据一致，这些数据显示塞瑞替尼在克唑替尼耐药疾病患者中具有显著疗效。
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378) in the setting of crizotinib resistance. Interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of crizotinib-resistant NSCLC patients revealed that ceritinib potently overcomes crizotinib resistance mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations were identified in 5 out of 11 biopsies from patients with acquired resistance to ceritinib. Altogether our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.