PMID- 30771617
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 2162-2531 (Print)
IS  - 2162-2531 (Electronic)
IS  - 2162-2531 (Linking)
VI  - 14
DP  - 2019 Mar 1
TI  - ERK Inhibitor Enhances Everolimus Efficacy through the Attenuation of dNTP Pools 
      in Renal Cell Carcinoma.
PG  - 550-561
LID - S2162-2531(19)30004-6 [pii]
LID - 10.1016/j.omtn.2019.01.001 [doi]
AB  - The clinical efficiency of everolimus, an mammalian target of rapamycin (mTOR) 
      inhibitor, is palliative as sequential or second-line therapy for renal cell 
      carcinoma (RCC). However, the limited response of everolimus in RCC remains 
      uncertain. In the present study, everolimus-resistant RCC models were established 
      to understand the mechanisms and to seek combination approaches. Consequently, 
      the activation of ERK was found to contribute toward everolimus-acquired 
      resistance and poor prognosis in patients with RCC. In addition, the efficacy and 
      mechanism of combination treatment underlying RCC using everolimus and ERK 
      inhibitors was investigated. The ERK inhibitor in combination with everolimus 
      synergistically inhibited the proliferation of RCC cells by arresting the cell 
      cycle in the G1 phase. The combination treatment markedly attenuated the 
      deoxyribonucleoside triphosphate (dNTP) pools by downregulating the mRNA 
      expression of RRM1 and RRM2 through E2F1. The overexpression of E2F1 or 
      supplementation of dNTP rescued the anti-proliferation activity of the 
      everolimus-SCH772984 combination. The antitumor efficacy of combination therapy 
      was reiterated in RCC xenograft models. Thus, the current findings provided 
      evidence that the everolimus-ERK inhibitor combination is a preclinical 
      therapeutic strategy for RCC.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Zou, Yun
AU  - Zou Y
AD  - Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of 
      Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
FAU - Li, Wenzhi
AU  - Li W
AD  - Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of 
      Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
FAU - Zhou, Juan
AU  - Zhou J
AD  - Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of 
      Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
FAU - Zhang, Jin
AU  - Zhang J
AD  - Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai 200127, China.
FAU - Huang, Yiran
AU  - Huang Y
AD  - Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai 200127, China. Electronic address: hyrrenji2@aliyun.com.
FAU - Wang, Zhong
AU  - Wang Z
AD  - Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of 
      Medicine, Shanghai Jiao Tong University, Shanghai 200011, China. Electronic 
      address: zhongwang2000@sina.com.
LA  - eng
PT  - Journal Article
DEP - 20190110
PL  - United States
TA  - Mol Ther Nucleic Acids
JT  - Molecular therapy. Nucleic acids
JID - 101581621
PMC - PMC6374702
OTO - NOTNLM
OT  - ERK inhibitor
OT  - dNTP
OT  - everolimus
OT  - renal cell carcinoma
OT  - ribonucleotide reductase
EDAT- 2019/02/17 06:00
MHDA- 2019/02/17 06:01
PMCR- 2019/01/10
CRDT- 2019/02/17 06:00
PHST- 2018/09/14 00:00 [received]
PHST- 2019/01/01 00:00 [revised]
PHST- 2019/01/01 00:00 [accepted]
PHST- 2019/02/17 06:00 [pubmed]
PHST- 2019/02/17 06:01 [medline]
PHST- 2019/02/17 06:00 [entrez]
PHST- 2019/01/10 00:00 [pmc-release]
AID - S2162-2531(19)30004-6 [pii]
AID - 10.1016/j.omtn.2019.01.001 [doi]
PST - ppublish
SO  - Mol Ther Nucleic Acids. 2019 Mar 1;14:550-561. doi: 10.1016/j.omtn.2019.01.001. 
      Epub 2019 Jan 10.