title: The selective MEK1 inhibitor Selumetinib enhances the antitumor activity of everolimus against renal cell carcinoma in vitro and in vivo.
abstract: Renal cell carcinoma (RCC) is a urologic malignant cancer and often diagnosed at an advanced stage, which results in high mortality. Targeted therapy may improve the quality of life and survival of patients who are not suitable for nephrectomy. Everolimus, an mTOR inhibitor, is currently used as sequential or second-line therapy for RCC refractory to Sunitinib or sorafenib. However, its efficiency is palliative. In this study, we evaluated whether the antitumor activity of everolimus against RCC is enhanced by Selumetinib, a selective MEK1 inhibitor. We discovered that everolimus in combination with Selumetinib synergistically inhibited the proliferation of Caki-1, 786-O and 769-P cells in vitro. Mechanistically, this combination decreased p-RPS6 and p-4E-BP1 dramatically, which causes G1 cell cycle arrest and prevents reactivation of AKT and ERK. In vivo, the antitumor efficacy and pharmacodynamic biomarkers of the combination therapy were recapitulated in Caki-1 xenograft model. In addition, this combination treatment potently inhibited angiogenesis in xenograft models by impairing VEGF secretion from tumor cells. Our findings provide a sound evidence that combination of everolimus and Selumetinib is a potential dual-targeted strategy for renal cell carcinoma.
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage; D014408:Biomarkers, Tumor; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D000068338:Everolimus; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human
keywords: Selumetinib; combination therapy; everolimus; renal cell carcinoma; targeted therapy