Targeting KRAS-Mutant Non-Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib
Targeting KRAS-Mutant Non-Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib
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DOI：
10.1158/1535-7163.mct-12-0615
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发表时间：
2012-12-01
影响因子：
5.7
通讯作者：
Proia, David A.
中科院分区：
文献类型：
--
作者：
Acquaviva, Jaime;Smith, Donald L.;Proia, David A.
突变型KRAS是超过25%的非小细胞肺癌（NSCLC）的特征，是这种疾病中最常见的致癌驱动因素之一。具有致癌KRAS的NSCLC肿瘤对当前疗法的反应较差，需要寻求新的治疗策略。分子伴侣Hsp90的靶向抑制导致肿瘤细胞中多种致癌信号通路的协同阻断，因此已成为人类恶性肿瘤治疗干预的有吸引力的途径。在这里，我们检查了ganetespib的活性，ganetespib是一种目前在NSCLC临床试验中的Hsp90小分子抑制剂，在一组具有不同KRAS突变谱的肺癌细胞系中。在体外，ganetespib在所有细胞系中均具有强效细胞毒性，伴随KRAS信号传导效应物的不稳定。低剂量ganetespib与MEK或PI3K/mTOR抑制剂的组合在突变KRAS细胞亚组中产生优于单药的细胞毒性活性，并且ganetespib的抗肿瘤功效通过与PI3K/mTOR抑制剂BEZ235在体内A549异种移植物中的共处理而增强。在分子水平上，ganetespib抑制了对MEK和PI3K/mTOR抑制反应的激活反馈信号循环，尽管这种活性不是组合获益的唯一决定因素。此外，ganetespib使突变型KRAS NSCLC细胞对抗有丝分裂剂、拓扑异构酶抑制剂和烷化剂类标准治疗化疗药物敏感。总之，这些数据强调了ganetespib作为KRAS驱动的肺肿瘤的单药或联合治疗的前景。Mol Cancer Ther; 11（12）; 2633 - 43.（C）2012年AACR。
Mutant KRAS is a feature of more than 25% of non-small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies, necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone Hsp90 results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90 currently in clinical trials for NSCLCs in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low-dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by cotreatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level, ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard-of-care chemotherapeutics of the antimitotic, topoisomerase inhibitor, and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single-agent or combination treatment in KRAS-driven lung tumors. Mol Cancer Ther; 11(12); 2633-43. (C)2012 AACR.