Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
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DOI：
10.1158/1078-0432.ccr-17-1192
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发表时间：
2017-11-01
影响因子：
11.5
通讯作者：
Christensen, James G.
中科院分区：
文献类型：
--
作者：
Engstrom, Lars D.;Aranda, Ruth;Christensen, James G.
目的：MET外显子14缺失(METEX 14 Del)突变代表了一类新的非小细胞肺癌(NSCLC)驱动突变。我们在METEX 14阳性的非临床模型和非小细胞肺癌患者中评估了格列沙替尼，一种表现为II型结合模式的光谱选择性MET抑制剂，并评估了其克服对I型MET抑制剂耐药的能力。实验设计：由于临床开发中的大多数MET抑制剂与I型结合模式结合活性部位，我们利用体外和体内模型以及格列沙替尼临床试验研究了对每种MET抑制剂类别获得性耐药的机制。结果：格列沙替尼抑制MET信号，显示METEX 14 del驱动的患者来源的异种移植物显著消退，并在参加格列沙替尼临床试验的METEX 14 del突变阳性患者中显示出持久的RECIST部分反应。用选定的MET抑制剂长期治疗非临床模型会导致耐药性动力学的差异和MET激活环路(即D1228N，Y1230C/H)内的突变，这些突变使人对I型MET抑制剂产生耐药性，但对格列沙替尼仍然敏感。在显示METEX 14 del/A环双重突变和对I型抑制剂耐药的活体模型中，格列沙替尼表现出显著的反应。最后，一名METEX 14 del突变阳性的非小细胞肺癌患者对克里佐替尼有反应，但后来复发，对格列沙替尼表现出混合反应，包括MET Y1230H突变阳性的肝转移灶缩小，同时在血浆DNA中检测不到该突变。结论：这些数据表明，格列沙替尼显示了一种独特的靶向抑制机制，可以克服对I型MET抑制剂的耐药性。(C)2017年AACR。
Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET-inhibitor exhibiting a type II binding mode, in METex14 delpositive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. (C) 2017 AACR.