FGFR3 Translocations in Bladder Cancer: Differential Sensitivity to HSP90 Inhibition Based on Drug Metabolism
FGFR3 Translocations in Bladder Cancer: Differential Sensitivity to HSP90 Inhibition Based on Drug Metabolism
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DOI：
10.1158/1541-7786.mcr-14-0004
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发表时间：
2014-07-01
影响因子：
5.2
通讯作者：
Proia, David A.
中科院分区：
文献类型：
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作者：
Acquaviva, Jaime;He, Suqin;Proia, David A.
FGFR 3的激活突变和/或过表达在膀胱癌中很常见，使得FGFR 3成为该疾病中有吸引力的治疗靶点。此外，最近已经描述了FGFR 3基因重排，其定义了膀胱肿瘤的独特子集。在此，选择性HSP 90抑制剂ganetespib诱导RT 112膀胱细胞中FGFR 3-TACC 3融合蛋白表达的丧失和多种致癌信号蛋白的耗竭，导致与泛FGFR酪氨酸激酶抑制剂BGJ 398相当的强效细胞毒性。然而，与BGJ 398相比，ganetespib对其他促有丝分裂和存活途径发挥多效性作用，并可克服表达FGFR 3突变体的97-7和MHG-U3细胞的FGFR突变体耐药表型。当ganetespib与BGJ 398在体外和体内一起使用时，观察到组合益处。有趣的是，另外两个FGFR 3融合阳性细胞系（RT 4和SW 480）对安莎霉素17-AAG和17-DMAG的HSP 90抑制剂处理保持敏感性，但对ganetespib或AUY 922（均为第二代间苯二酚化合物）显示出内在耐药性。与RT 112相比，两种细胞系均表达了显著更高水平的内源性UGT 1A酶;该表型导致了快速的葡萄糖醛酸化依赖性代谢和随后的ganetespib从SW 780细胞中流出，从而提供了一种解释缺乏生物活性的机制。(C)2014年AACR。
Activating mutations and/or overexpression of FGFR3 are common in bladder cancer, making FGFR3 an attractive therapeutic target in this disease. In addition, FGFR3 gene rearrangements have recently been described that define a unique subset of bladder tumors. Here, a selective HSP90 inhibitor, ganetespib, induced loss of FGFR3-TACC3 fusion protein expression and depletion of multiple oncogenic signaling proteins in RT112 bladder cells, resulting in potent cytotoxicity comparable with the pan-FGFR tyrosine kinase inhibitor BGJ398. However, in contrast to BGJ398, ganetespib exerted pleiotropic effects on additional mitogenic and survival pathways and could overcome the FGFR inhibitor-resistant phenotype of FGFR3 mutant-expressing 97-7 and MHG-U3 cells. Combinatorial benefit was observed when ganetespib was used with BGJ398 both in vitro and in vivo. Interestingly, two additional FGFR3 fusion-positive lines (RT4 and SW480) retained sensitivity to HSP90 inhibitor treatment by the ansamycins 17-AAG and 17-DMAG yet displayed intrinsic resistance to ganetespib or AUY922, both second-generation resorcinol-based compounds. Both cell lines, compared with RT112, expressed considerably higher levels of endogenous UGT1A enzyme; this phenotype resulted in a rapid glucuronidation-dependent metabolism and subsequent efflux of ganetespib from SW780 cells, thus providing a mechanism to account for the lack of bioactivity. (C) 2014 AACR.