title: Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma.
abstract: Here we found that dual mTORC1/2 inhibitor AZD-2014 significantly inhibited RCC cell survival and growth, with higher efficiency than conventional mTORC1 inhibitors rapamycin and RAD001. RCC cell apoptosis was also induced by AZD-2014. AZD-2014 disrupted mTORC1/2 assembly and activation, while downregulating HIF-1α/2α and cyclin D1 expressions in RCC cells. Meanwhile, AZD-2014 activated autophagy, detected by p62 degradation, Beclin-1/ATG-5 upregulation and light LC3B-I/-II conversion. Autophagy inhibition by pharmacologic or siRNA-based means increased AZD-2014 activity in vitro, causing substantial RCC cell apoptosis. In vivo, AZD-2014 was more efficient than RAD001 in inhibiting 786-0 xenografts and downregulating HIF-1α/2α or p-AKT (Ser-473). Finally, AZD-2014's activity in vivo was further enhanced by co-administration of the autophagy inhibitor 3-methyaldenine. We provide evidence for clinical trials of using AZD-2014 in RCC treatment.
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China. Electronic address: bingzhengnantong@163.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of pathophysiology, Nantong University School of Medicine, Nantong, China.
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Dong-hua
authors.initials: DH
authors.lastname: Gu
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Pan
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Shanghai Institute for Kidney and Dialysis, Fudan University, Shanghai, China. Electronic address: fang.yi@zs-hospital.sh.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Yi
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: jidongmei2000@126.com.
authors.forename: Dong-mei
authors.initials: DM
authors.lastname: Ji
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001549:Benzamides; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines; D034622:RNA Interference; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001549:Benzamides; D019938:Cyclin D1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C585537:vistusertib
keywords: AZD-2014; Autophagy; Renal cell carcinoma; Sensitization and hypoxia-inducible factor; mTOR