title: Potential biomarkers for the therapeutic efficacy of sorafenib, sunitinib and everolimus.
abstract: We examined extracellular signal‑regulated kinase (ERK), 4E‑binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70) as potential biomarkers for pretreatment prediction of the prognosis of patients with metastatic renal cell carcinoma (RCC) treated with sorafenib, sunitinib or everolimus. 786‑O and 769‑P cells were treated with sorafenib, sunitinib and everolimus. The expression of phosphorylated/total ERK, phosphorylated/total 4EBP1 and phosphorylated/total p70 was evaluated using western blotting. ERK, 4EBP1 and p70 were knocked down by siRNA in 786‑O and 769‑P cells. Then, the viability after treatment with each drug was assessed. Expression of phosphorylated (phospho)‑ERK, -4EBP1 and -p70 was immunohistochemically evaluated in radical nephrectomy specimens and correlated with progression‑free survival during treatment with each molecular targeting agent. Sorafenib inhibited the expression of phospho-ERK and -4EBP1 in 769‑P cells; sunitinib, phospho-ERK and -4EBP1 in 786‑O and 769‑P cells; and everolimus, phospho-p70 in 786‑O and 769‑P cells. Knockdown of ERK reduced sensitivity to sorafenib in both cell lines, knockdown of ERK and 4EBP1 reduced sensitivity to sunitinib in 769‑P cells, and knockdown of 4EBP1 and p70 reduced sensitivity to everolimus in 786‑O cells. High expression of phospho-ERK, -4EBP1 and -p70 correlated with better progression‑free survival in patients treated with sorafenib, sunitinib and everolimus, respectively. Our results indicate that phospho-ERK, -4EBP1 and/or -ERK, and phospho-p70 can be used as biomarkers for the therapeutic efficacy of sorafenib, sunitinib and everolimus, respectively.
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Makito
authors.initials: M
authors.lastname: Miyake
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Morizawa
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Shunta
authors.initials: S
authors.lastname: Hori
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tatsumi
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Anai
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Onishi
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Kiyohide
authors.initials: K
authors.lastname: Fujimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D000068338:Everolimus / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007211:Indoles; D010671:Phenylurea Compounds; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D000077210:Sunitinib