The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and -resistant MET-driven tumor models.
The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and -resistant MET-driven tumor models.
复制标题
Hsp90抑制剂Ganetespib在crizotinib敏感和耐抗MET驱动的肿瘤模型中与MET激酶抑制剂Crizotinib协同作用。
DOI：
10.1158/0008-5472.can-13-1156
复制
发表时间：
2013-12-01
期刊：
影响因子：
11.2
通讯作者：
Neckers L
中科院分区：
文献类型：
--
作者：
Miyajima N;Tsutsumi S;Sourbier C;Beebe K;Mollapour M;Rivas C;Yoshida S;Trepel JB;Huang Y;Tatokoro M;Shinohara N;Nonomura K;Neckers L
原癌基因MET在许多癌症中通过过度表达或突变而异常激活，使其成为主要的抗癌分子靶点。然而，MET导向的酪氨酸激酶抑制剂（TKI）的临床成功受到限制，部分原因是MET激酶结构域的突变导致了治疗耐药性。规避这一问题仍然是改善接受met靶向治疗的患者持久反应的关键挑战。MET是一种依赖于HSP90的激酶，在本报告中，我们发现HSP90优先与活化的MET相互作用并使其稳定，而不管活化是依赖于配体还是激酶结构域突变的结果。相反，许多MET- tki表现出对激酶的非活性形式的偏好，并且MET的激活突变可以赋予抗性。将HSP90抑制剂ganetespib与MET- tki克里唑替尼联合使用，在tki敏感和耐药的MET驱动肿瘤模型中实现了MET、其下游信号通路和肿瘤生长的协同抑制。这些数据表明，纳入HSP90抑制剂可以部分恢复TKI对先前耐药MET突变体的敏感性，并为MET驱动型癌症患者的这种治疗组合的临床评估提供了基础。
The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving MET-targeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers.