Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor.
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.
Bauer
Sebastian
S
Department of Pathology, Brigham and Women's Hospital, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, and Ludwig Center at Dana Farber/Harvard Cancer Center, Boston, Massachusetts 02115, USA.
Yu
Lynn K
LK
Demetri
George D
GD
Fletcher
Jonathan A
JA
D001549:Benzamides; D016227:Benzoquinones / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction
D001549:Benzamides; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C112765:tanespimycin; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit