胃肠间质瘤治疗中HSP90抑制剂的应用

doi:10.3877/cma.j.issn.2095-3224.2019.03.014

随着酪氨酸激酶受体抑制剂（TKI）伊马替尼等靶向治疗药物的发明，胃肠间质瘤（GIST）的生存期大为改善，但GIST的原发和继发性耐药问题是限制其疗效的关键。热休克蛋白90（HSP90）抑制剂能绕过酪氨酸激酶受体，直接作用于其下游信号分子的保护伞HSP90，间接使其下游信号分子降解，中断异常活化的信号通路，从而抑制GIST的生长。近年来，HSP90抑制剂作为GIST三线治疗药物开始尝试应用于临床实验。研究表明，多种HSP90抑制剂对TKI多重耐药的GIST患者有较好疗效。随着药理学、分子生物学、生物信息学等学科的不断发展和相互促进，BEAMing技术等新一代测序技术的应用，HSP90抑制剂的应用前景会渐趋光明。

关键词: 结直肠肿瘤, 胃肠间质瘤, HSP90抑制剂, 临床应用, 酪氨酸激酶受体抑制剂

With the development of targeted therapeutics such as Tyrosine Kinase Receptor inhibitors (TKI) Imatinib, the treatment of rare diseases such as gastrointestinal stromal tumors (GIST) is certainly to the extent that there has been no cure for medicine, the drug has become ″drug to disease,″ but the problems of primary and secondary resistance to gastrointestinal stromal tumors and when it is possible to stop the drug are the key to limite the further improvement to fit sefficacy. Heat shock protein90 (HSP90) inhibitor scan by pass tyrosine kinase receptors and directly act on the protective umbrella HSP90 of the down stream signaling molecules, indirectly degrading down stream signaling molecules and disrupting abnormally activated signaling pathways. This inhibits the growth of gastrointestinal stromal tumors. In recent years, HSP90 inhibitors have been used in clinical trials as a third-line treatment for gastrointestinal stromal tumors. With the continuous development and mutual promotion of pharmacology, molecular biology, bioinformatics and other disciplines, application of next-generation sequencing technology such as BEAMing technology, the application prospects of HSP90 inhibitors will gradually become brighter.

Key words: Colorectal neoplasms, GIST, HSP90 inhibitor, Clinical application, Tyrosine kinase receptor inhibitors (TKI)

表1 胃肠间质瘤相关治疗靶点的临床研究

类别	药物名称	研究编号
KIT和PDGFRA酪氨酸激酶抑制剂	Masitinib（AB1010）	NCT00998751（U）
	Crenolanib （CP-868，596）	NCT02847429（R），NCT01243346 （C）
	AZD2171	NCT00385203（C）
	Vatalanib（PTK787）	NCT00117299（C），NCT00655655 （A）
	OSI-930	NCT00513851（C）
	TKI258	NCT01478373（C），NCT01440959 （C）
	DCC-2618	NCT02571036（R）
KIT和PDGFRA生物抑制剂	Olaratumab（IMC-3G3）	NCT01316263（C）
HSP90抑制剂	Retaspimycin（IPI-5040）	NCT00276302（C），NCT00688766 （T）
	BIIB021（CNF2024）	NCT00618319（C）
	Ganetespib（STA-9090）	NCT01039519（C）
	AUY922	NCT01389583（R），NCT01404650 （C）
	AT13387	NCT01294202（C）
KIT和PDGFRA下游旁路抑制剂	RAS/RAF/MEK/ERK/MAPKinhibitors：MEK162	NCT01991379
	AKTinhibitors：perifosine	NCT00455559（C）
	mTORinhibitors：everolimus（RAD001）	NCT01275222（C），NCT00510354 （C），NCT02071862（R）
	mTORinhibitors：temsirolimus（Torisel）	NCT00700258（R）
细胞周期抑制剂	Alvocidib（Flavopiridol）	NCT00098579（C）
胰岛素样生长因子旁路抑制剂	OSI-906	NCT01560260（C）

表1 胃肠间质瘤相关治疗靶点的临床研究

类别	药物名称	研究编号
KIT和PDGFRA酪氨酸激酶抑制剂	Masitinib（AB1010）	NCT00998751（U）
	Crenolanib （CP-868，596）	NCT02847429（R），NCT01243346 （C）
	AZD2171	NCT00385203（C）
	Vatalanib（PTK787）	NCT00117299（C），NCT00655655 （A）
	OSI-930	NCT00513851（C）
	TKI258	NCT01478373（C），NCT01440959 （C）
	DCC-2618	NCT02571036（R）
KIT和PDGFRA生物抑制剂	Olaratumab（IMC-3G3）	NCT01316263（C）
HSP90抑制剂	Retaspimycin（IPI-5040）	NCT00276302（C），NCT00688766 （T）
	BIIB021（CNF2024）	NCT00618319（C）
	Ganetespib（STA-9090）	NCT01039519（C）
	AUY922	NCT01389583（R），NCT01404650 （C）
	AT13387	NCT01294202（C）
KIT和PDGFRA下游旁路抑制剂	RAS/RAF/MEK/ERK/MAPKinhibitors：MEK162	NCT01991379
	AKTinhibitors：perifosine	NCT00455559（C）
	mTORinhibitors：everolimus（RAD001）	NCT01275222（C），NCT00510354 （C），NCT02071862（R）
	mTORinhibitors：temsirolimus（Torisel）	NCT00700258（R）
细胞周期抑制剂	Alvocidib（Flavopiridol）	NCT00098579（C）
胰岛素样生长因子旁路抑制剂	OSI-906	NCT01560260（C）

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Application of HSP90 inhibitors in the treatment of gastrointestinal stromal tumors

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