Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib.
BACKGROUND
Sorafenib, a multitarget kinase inhibitor, inhibits members of the mitogen-activated protein kinase (MAPK) pathway and receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGF-R2). Sorafenib, carboplatin, and paclitaxel (SCP) has antitumor activity in melanoma patients, but no association was found between response and activating B-Raf V600E mutations. We assessed the expression of sorafenib targets in SCP-treated patient specimens and evaluated the association with response and progression-free survival.


METHODS
Using automated quantitative analysis, we quantified the expression of VEGF-R1, VEGF-R2, VEGF-R3, fibroblast growth factor receptor 1, platelet-derived growth factor receptor beta, c-Kit, B-Raf, C-Raf, meiosis-specific serine/threonine protein kinase 1, and extracellular regulated kinase 1/2 (ERK1/2) in pretreatment specimens from 46 patients. Furthermore, we assessed ERK1/2 expression in 429 archival melanomas.


RESULTS
VEGF-R2 expression was significantly higher in patients with a complete or partial response (P = 0.0435), whereas ERK1/2 was higher in patients who did not respond (P = 0.0417). High ERK1/2 was an independent predictor of poor survival. High ERK1/2 was associated with decreased survival in the archival melanoma cohort, suggesting that high ERK1/2-expressing tumors are biologically more aggressive. All of the six patients with both high VEGF-R2 and low ERK1/2 responded to SCP.


CONCLUSIONS
High VEGF-R2 expression is associated with response to SCP in melanoma, whereas high ERK1/2 is associated with resistance. Collection of specimens from SCP-treated melanoma patients in a cooperative group phase III trial comparing this regimen with the chemotherapy alone is ongoing, and confirmation of these findings is necessary. These markers might be useful for predicting response to sorafenib when given with other chemotherapies and in other diseases, resulting in the possible elimination of unnecessary treatment of patients unlikely to respond.
Jilaveanu
Lucia
L
Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Zito
Christopher
C
Lee
Sandra J
SJ
Nathanson
Katherine L
KL
Camp
Robert L
RL
Rimm
David L
DL
Flaherty
Keith T
KT
Kluger
Harriet M
HM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage*; D016190:Carboplatin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D016503:Drug Delivery Systems; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009536:Niacinamide / Q000031:analogs & derivatives; D017239:Paclitaxel / Q000008:administration & dosage*; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D000077157:Sorafenib; D016896:Treatment Outcome
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D016190:Carboplatin; D040262:Receptors, Vascular Endothelial Growth Factor; D048052:Mitogen-Activated Protein Kinase 3; D017239:Paclitaxel