Abstract
Heat shock protein 90 (HSP90) is involved in the regulation of diverse biological processes such as cell signaling, proliferation and survival, and has been recently recognized as a potential target for cancer therapy. Ganetespib is a potent ATP competitive inhibitor of HSP90. Ganetespib downregulated the expression of multiple signal transducing molecules including EGFR, IGF-1R, c-Met, Akt, B-RAF and C-RAF, resulting in pronounced decrease in phosphorylation of Akt and Erk1/2 in a panel of five cutaneous melanoma cell lines including those harboring B-RAF and N-RAS mutations. Ganetespib exhibited potent antiproliferative activity on all five of these cell lines, with IC50 values between 37.5 and 84 nM. Importantly, Ganetespib is active on B-RAF mutated melanoma cells that have acquired resistance to B-RAF inhibition. Ganetespib induced apoptosis and cell cycle arrest at G1 and/or G2/M phase. Ganetespib induced cell cycle arrest was accompanied by altered expression of cyclin-dependent kinase inhibitor (CDKI) p21(Cip1) and p27(Kip1), cyclins B1, D1 and E, and/or cyclin-dependent kinases 1, 2 and 4. HSP90 is functionally important for melanoma cells and HSP90 inhibitors such as ganetespib could potentially be effective therapeutics for melanoma with various genetic mutations and acquired resistance to B-RAF inhibition.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Apoptosis / drug effects*
-
Cell Cycle Checkpoints / drug effects*
-
Cell Cycle Proteins / metabolism
-
Cell Line, Tumor
-
Cell Proliferation / drug effects*
-
Cell Survival / drug effects
-
Down-Regulation / drug effects
-
ErbB Receptors / metabolism
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
GTP Phosphohydrolases / genetics
-
GTP Phosphohydrolases / metabolism
-
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
-
HSP90 Heat-Shock Proteins / metabolism
-
Humans
-
Immunoblotting
-
Inhibitory Concentration 50
-
Melanoma / genetics
-
Melanoma / metabolism
-
Melanoma / pathology
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism
-
Mutation
-
Phosphorylation / drug effects
-
Proto-Oncogene Proteins B-raf / genetics
-
Proto-Oncogene Proteins B-raf / metabolism
-
Proto-Oncogene Proteins c-akt
-
Receptor, IGF Type 1 / metabolism
-
Skin Neoplasms / genetics
-
Skin Neoplasms / metabolism
-
Skin Neoplasms / pathology
-
Triazoles / pharmacology*
Substances
-
Cell Cycle Proteins
-
HSP90 Heat-Shock Proteins
-
Membrane Proteins
-
STA 9090
-
Triazoles
-
ErbB Receptors
-
Receptor, IGF Type 1
-
BRAF protein, human
-
Proto-Oncogene Proteins B-raf
-
Proto-Oncogene Proteins c-akt
-
Extracellular Signal-Regulated MAP Kinases
-
GTP Phosphohydrolases
-
NRAS protein, human
Grants and funding
This work was supported in part by Sharon Crowley Martin Memorial Fund for Melanoma Research (F. S. Hodi), the Malcolm and Emily Mac Naught Fund for Melanoma Research (F. S. Hodi) at Dana-Farber Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.