Zhu Viola W, Nagasaka Misako, Madison Russell, Schrock Alexa B, Cui Jean, Ou Sai-Hong Ignatius
Chao Family Comprehensive Cancer Center, Department of Medicine, Divison of Hematology/Oncology, University of California Irvine School of Medicine, Orange, California.
Karmanos Cancer Institute, Department of Medical Oncology, Wayne State University School of Medicine, Detroit, Michigan.
JTO Clin Res Rep. 2020 Nov 21;2(1):100116. doi: 10.1016/j.jtocrr.2020.100116. eCollection 2021 Jan.
Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved variant 3 G1202R/S1206Y double mutation in detected in a patient with -positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib ( G1202R/L1196M, G1202R/F1174C, G1202R/l1198F, G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments.
劳拉替尼是一种第三代ALK抑制剂，能够克服数量最多的获得性耐药突变，包括溶剂前沿突变G1202R。在此，我们首次报告了一名ALK阳性非小细胞肺癌患者在先后接受克唑替尼、阿来替尼，然后是劳拉替尼治疗疾病进展后检测到的一种新型的、顺序进化的变体3 G1202R/S1206Y双重突变。提供了这种双重突变以及其他基于G1202R的双重突变（G1202R/L1196M、G1202R/F1174C、G1202R/l1198F、G1202R/G1269A）与劳拉替尼的三维计算机建模，以揭示这些双重突变如何通过ALK激酶结构域中不同的空间位阻赋予对劳拉替尼的耐药性。此外，我们对已发表的来自患者样本和体外诱变实验的对劳拉替尼耐药的获得性双重或三重突变进行了全面的文献综述。
