Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor

被引:220
作者
Bauer, Sebastian
Yu, Lynn K.
Demetri, George D.
Fletcher, Jonathan A.
机构
[1] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[2] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA
[3] Harvard Univ, Ctr Canc, Dana Farber Canc Inst, Ludwig Ctr, Boston, MA 02115 USA
关键词
D O I
10.1158/0008-5472.CAN-06-0165
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Inhibition of KIT oncoproteins by imatinib induces clinical responses in most gastrointestinal stromal tumor (GIST) patients. However, many patients develop imatinib resistance due to secondary KIT mutations. Heat shock protein 90 (HSP90) protects KIT oncoproteins from proteasome-mediated degradation, and we therefore did preclinical validations of the HSP90 inhibitor, 17-allylamino-18-demethoxy-geldanamycin (17-AAG), in an imatinib-sensitive GIST cell line (GIST882) and in novel imatinib-resistant GIST lines that are either dependent on (GIST430 and GIST48) or independent of (GIST62) KIT oncoproteins. 17AAG (> 100 nmol/L) inhibited imatinib-sensitive and imatinib-resistant KIT oncoproteins, with substantially reduced phospho-KIT and total KIT expression after 30 minutes and 6 hours, respectively. KIT signaling intermediates, including AKT and mitogen-activated protein kinase, were inactivated by 17-AAG in the KIT-positive GIST lines, but not in the KIT-negative GIST62. Likewise, cell proliferation and survival were inhibited in the KIT-positive GISTs but not in GIST62. These findings suggest that 17-AAG biological effects in KIT-positive GISTs result mainly from KIT oncoprotein inhibition. The dramatic inactivation of imatinib-resistant KIT oncoproteins suggests that HSP90 inhibition provides a therapeutic solution to the challenge of heterogeneous imatinib resistance mutations in GIST patients.
引用
收藏
页码:9153 / 9161
页数:9
相关论文
共 43 条
  • [1] An WG, 2000, CELL GROWTH DIFFER, V11, P355
  • [2] Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies
    Banerji, U
    O'Donnell, A
    Scurr, M
    Pacey, S
    Stapleton, S
    Asad, Y
    Simmons, L
    Maloney, A
    Raynaud, F
    Campbell, M
    Walton, M
    Lakhani, S
    Kaye, S
    Workman, P
    Judson, I
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (18) : 4152 - 4161
  • [3] BAUER S, 2005, P AN M AM SOC CLIN, V23, pA9034
  • [4] The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy
    Blagosklonny, MV
    Fojo, T
    Bhalla, KN
    Kim, JS
    Trepel, JB
    Figg, WD
    Rivera, Y
    Neckers, LM
    [J]. LEUKEMIA, 2001, 15 (10) : 1537 - 1543
  • [5] Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia
    Cho, JY
    Guo, CS
    Torello, M
    Lunstrum, GP
    Iwata, T
    Deng, CX
    Horton, WA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (02) : 609 - 614
  • [6] Adult pancreas generates multipotent stem cells and pancreatic and nonpancreatic progeny
    Choi, Y
    Ta, M
    Atouf, F
    Lumelsky, N
    [J]. STEM CELLS, 2004, 22 (06) : 1070 - 1084
  • [7] KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size
    Corless, CL
    McGreevey, L
    Haley, A
    Town, A
    Heinrich, MC
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2002, 160 (05) : 1567 - 1572
  • [8] THE USE OF ATP BIOLUMINESCENCE AS A MEASURE OF CELL-PROLIFERATION AND CYTOTOXICITY
    CROUCH, SPM
    KOZLOWSKI, R
    SLATER, KJ
    FLETCHER, J
    [J]. JOURNAL OF IMMUNOLOGICAL METHODS, 1993, 160 (01) : 81 - 88
  • [9] The 90-kDa molecular chaperone family:: Structure, function, and clinical applications.: A comprehensive review
    Csermely, P
    Schnaider, T
    Soti, C
    Prohászka, Z
    Nardai, G
    [J]. PHARMACOLOGY & THERAPEUTICS, 1998, 79 (02) : 129 - 168
  • [10] DESCRIPTION AND ANTIBIOTIC PRODUCTION OF STREPTOMYCES-HYGROSCOPICUS VAR GELDANUS
    DEBOER, C
    DIETZ, A
    [J]. JOURNAL OF ANTIBIOTICS, 1976, 29 (11) : 1182 - 1188