title: Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib.
abstract: Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF(V600E) inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF(V600E) mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF(V600E) provided combinatorial benefit in vemurafenib-sensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF(V600E) by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAF(V600E)-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors.
authors.affiliation: Corresponding Author: David A. Proia, Synta Pharmaceuticals Corp, 125 Hartwell Avenue, Lexington, MA 02421. dproia@syntapharma.com.
authors.forename: Jaime
authors.initials: J
authors.lastname: Acquaviva
authors.forename: Donald L
authors.initials: DL
authors.lastname: Smith
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Jimenez
authors.forename: Chaohua
authors.initials: C
authors.lastname: Zhang
authors.forename: Manuel
authors.initials: M
authors.lastname: Sequeira
authors.forename: Suqin
authors.initials: S
authors.lastname: He
authors.forename: Jim
authors.initials: J
authors.lastname: Sang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bates
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D011728:Pyridones; D011744:Pyrimidinones; C533237:STA 9090; D013449:Sulfonamides; C558666:TAK 733; D014230:Triazoles; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases