ErbB2 overexpression in an ovarian cancer cell line confers sensitivity to the HSP90 inhibitor geldanamycin.
ErbB2 is overexpressed in 25-30% of breast and ovarian cancers, correlates with poor prognosis and lower survival and has also been associated with chemoresistance. We have established an isogenic pair of human ovarian cells that differ only in the expression of erbB2 protein in order to elucidate the role of the protein in determining cellular sensitivity to various drugs and agents. These included cisplatin and paclitaxel, the main drugs used in the treatment of ovarian cancer, and also various signal transduction inhibitors affecting the ras and P13K pathways. Transfection of erbB2 resulted in cells stably overexpressing the protein and showing increased motility compared to the empty vector control cells. In cells overexpressing erbB2, the most notable effect on chemosensitivity was that of significantly increased (5-fold) sensitivity to the heat shock protein 90 (HSP90) molecular chaperone inhibitor geldanamycin. In contrast, erbB2-overexpressing cells showed statistically significant resistance to cisplatin, the P13K inhibitor LY294002 and the tyrosine kinase inhibitor emodin. No significant difference in growth inhibition was observed after exposure to paclitaxel, two additional HSP90 inhibitors radicicol and 17AAG, the cyclin-dependent kinase inhibitor flavopiridol, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor PD153035, the mek inhibitor U0126 or the famesyl transferase inhibitor R115777. Exposure of cells to geldanamycin, 17AAG, emodin, LY294002 and cisplatin led to depletion of erbB2 in the transfected cells. These data suggest that erbB2 status in ovarian cancr may contribute to chemosensitivity, in some cases leading to increased sensitivity (as with geldanamycin) but in other cases leading to resistance (as with cisplatin).
Smith
Vicki
V
CRC Center for Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.
Hobbs
Stephen
S
Court
William
W
Eccles
Suzanne
S
Workman
Paul
P
Kelland
Lloyd R
LR
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity; D016227:Benzoquinones; D002867:Chromones / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D004642:Emodin / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D018734:Genes, erbB-2; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D009025:Morpholines / Q000633:toxicity; D011809:Quinones / Q000633:toxicity*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D016227:Benzoquinones; D002867:Chromones; D002945:Cisplatin; D004642:Emodin; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009025:Morpholines; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C001277:geldanamycin