Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.
Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.
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DOI：
10.1056/nejmoa1508887
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发表时间：
2016-01-07
期刊：
影响因子：
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通讯作者：
Engelman JA
中科院分区：
文献类型：
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作者：
Shaw AT;Friboulet L;Leshchiner I;Gainor JF;Bergqvist S;Brooun A;Burke BJ;Deng YL;Liu W;Dardaei L;Frias RL;Schultz KR;Logan J;James LP;Smeal T;Timofeevski S;Katayama R;Iafrate AJ;Le L;McTigue M;Getz G;Johnson TW;Engelman JA
在1例转移性间变性淋巴瘤激酶（ALK）重排肺癌患者中，由于ALK激酶结构域的突变而对克唑替尼产生耐药。预测该突变导致氨基酸残基1156处的半胱氨酸被酪氨酸取代（C1156 Y）。她的肿瘤对第二代ALK抑制剂没有反应，但对第三代抑制剂劳拉替尼（PF-06463922）有反应。当她的肿瘤复发时，耐药肿瘤的测序显示除了C1156 Y突变之外还有ALK L1198 F突变。L1198 F取代通过对药物结合的空间干扰赋予对劳拉替尼的耐药性。然而，L1198 F矛盾地增强了与克唑替尼的结合，抵消了C1156 Y的作用，并使耐药癌症对克唑替尼重新敏感。患者再次接受克唑替尼治疗，其癌症相关症状和肝功能衰竭消退。
In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved.