The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.
The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.
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DOI：
10.1158/1078-0432.ccr-11-2612
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发表时间：
2012-05-01
期刊：
影响因子：
--
通讯作者：
Smalley KS
中科院分区：
文献类型：
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作者：
Paraiso KH;Haarberg HE;Wood E;Rebecca VW;Chen YA;Xiang Y;Ribas A;Lo RS;Weber JS;Sondak VK;John JK;Sarnaik AA;Koomen JM;Smalley KS
BRAF抑制剂的临床应用受到耐药性获得的阻碍。本研究证明了HSP90抑制剂（XL888）在6种不同的vemurafenib耐药模型中的潜在治疗效用。体外和体内实验证实XL888能够抑制vemurafenib耐药黑色素瘤细胞系的生长、诱导细胞凋亡和肿瘤消退。在黑色素瘤细胞系、异种移植物和黑色素瘤活检中，一种新的基于质谱的药效学方法被开发出来，用于测量HSP90抑制后瘤内HSP70水平。通过机制研究确定xl888诱导细胞凋亡的机制。XL888在3D细胞培养、长期集落形成实验和人黑色素瘤小鼠异种移植实验中均能有效抑制vemurafenib耐药黑色素瘤细胞系的生长、诱导细胞凋亡和抑制细胞生长。耐药表型的逆转与PDGFRβ、COT、IGFR1、CRAF、ARAF、S6、cyclin D1和AKT的降解有关，进而导致FOXO3a的核积累、BIM表达的增加和Mcl-1的下调。在大多数耐药模型中，XL888处理比MEK/PI3K双重抑制更有效地增加了BIM表达，降低了Mcl-1表达，并诱导了细胞凋亡。抑制HSP90可能是一种非常有效的策略，可以管理BRAF抑制剂的多种耐药机制，并且在恢复BIM表达和下调Mcl-1表达方面似乎比MEK/PI3K抑制剂联合治疗更有效。
The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study demonstrates the potential therapeutic utility of the HSP90 inhibitor (XL888) in 6 different models of vemurafenib resistance. The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was demonstrated in vitro and in vivo. A novel mass spectrometry-based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts and melanoma biopsies. Mechanistic studies were performed to determine the mechanism of XL888-induced apoptosis. XL888 potently inhibited cell growth, induced apoptosis and prevented the growth of vemurafenib resistant melanoma cell lines in 3D cell culture, long-term colony formation assays and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the degradation of PDGFRβ, COT, IGFR1, CRAF, ARAF, S6, cyclin D1 and AKT, which in turn led to the nuclear accumulation of FOXO3a, an increase in BIM expression and the downregulation of Mcl-1. In most resistance models, XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual MEK/PI3K inhibition. HSP90 inhibition may be a highly effective strategy at managing the diverse array of resistance mechanisms being reported to BRAF inhibitors and appears to be more effective at restoring BIM expression and downregulating Mcl-1 expression than combined MEK/PI3K inhibitor therapy.