Acquired resistance to crizotinib from a mutation in CD74-ROS1.
Acquired resistance to crizotinib from a mutation in CD74-ROS1.
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从CD74-ROS1中的突变中获得了对克唑替尼的抗性。
DOI：
10.1056/nejmoa1215530
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发表时间：
2013-06-20
期刊：
影响因子：
--
通讯作者：
Shaw AT
中科院分区：
文献类型：
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作者：
Awad MM;Katayama R;McTigue M;Liu W;Deng YL;Brooun A;Friboulet L;Huang D;Falk MD;Timofeevski S;Wilner KD;Lockerman EL;Khan TM;Mahmood S;Gainor JF;Digumarthy SR;Stone JR;Mino-Kenudson M;Christensen JG;Iafrate AJ;Engelman JA;Shaw AT
Crizotinib 是一种间变性淋巴瘤激酶 (ALK) 抑制剂，最近也显示出治疗 ROS1 易位肺癌的功效。一名携带 CD74-ROS1 重排的转移性肺腺癌患者出现了对克唑替尼的耐药性，该患者最初对治疗表现出显着的反应。我们对耐药肿瘤进行了活检，发现了一种获得性突变，导致 ROS1 激酶结构域中的密码子 2032 处甘氨酸替换为精氨酸。尽管这种突变并不位于看门残基处，但它通过对药物结合的空间干扰而赋予对 ROS1 激酶抑制的抗性。在尸检检查的所有转移位点都观察到相同的抗性突变，表明这种突变是抗性克隆进化的早期事件。 （由辉瑞和其他公司资助；ClinicalTrials.gov 编号，NCT00585195。）
Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74–ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the meta-static sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)