Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.
Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.
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DOI：
10.1158/2159-8290.cd-16-0596
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发表时间：
2016-10
期刊：
影响因子：
28.2
通讯作者：
Shaw AT
中科院分区：
文献类型：
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作者：
Gainor JF;Dardaei L;Yoda S;Friboulet L;Leshchiner I;Katayama R;Dagogo-Jack I;Gadgeel S;Schultz K;Singh M;Chin E;Parks M;Lee D;DiCecca RH;Lockerman E;Huynh T;Logan J;Ritterhouse LL;Le LP;Muniappan A;Digumarthy S;Channick C;Keyes C;Getz G;Dias-Santagata D;Heist RS;Lennerz J;Sequist LV;Benes CH;Iafrate AJ;Mino-Kenudson M;Engelman JA;Shaw AT
目前，晚期间变性淋巴瘤激酶(ALK)阳性肺癌的治疗方法是第一代ALK抑制剂Crizotinib，随后是更有效的第二代ALK抑制剂(如Ceritinib，alectinib)。第二代抑制剂即使在没有耐药的ALK突变的情况下通常也是有效的，这可能反映了在许多情况下Crizotinib对ALK的不完全抑制。在这里，我们分析了103例ALK阳性患者的重复活检，这些患者正在接受各种ALK抑制剂的治疗。我们发现，每种ALK抑制剂都与不同的ALK耐药突变谱相关联，并且在第二代药物治疗后，一个突变-ALK G1202R-的频率显著增加。为了研究克服对第二代ALK抑制剂耐药性的策略，我们检测了第三代ALK抑制剂劳拉替尼在一系列对Ceritinib耐药的患者来源的细胞系中的活性，并观察到ALK耐药突变的存在对劳拉替尼的敏感性具有很高的预测性，而那些没有ALK突变的细胞系是耐药的。
Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation - ALK G1202R - increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.