PMID- 34421360
OWN - NLM
STAT- MEDLINE
DCOM- 20220318
LR  - 20240226
IS  - 1449-2288 (Electronic)
IS  - 1449-2288 (Linking)
VI  - 17
IP  - 12
DP  - 2021
TI  - Rapamycin and trametinib: a rational combination for treatment of NSCLC.
PG  - 3211-3223
LID - 10.7150/ijbs.62752 [doi]
AB  - Mammalian target of rapamycin (mTOR) is one of the most commonly activated 
      pathways in human cancers, including lung cancer. Targeting mTOR with molecule 
      inhibitors is considered as a useful therapeutic strategy. However, the results 
      obtained from the clinical trials with the inhibitors so far have not met the 
      original expectations, largely because of the drug resistance. Thus, combined or 
      multiple drug therapy can bring about more favorable clinical outcomes. Here, we 
      found that activation of ERK pathway was responsible for rapamycin drug 
      resistance in non-small-cell lung cancer (NSCLC) cells. Accordingly, 
      rapamycin-resistant NSCLC cells were more sensitive to ERK inhibitor (ERKi), 
      trametinib, and in turn, trametinib-resistant NSCLC cells were also susceptible 
      to rapamycin. Combining rapamycin with trametinib led to a potent synergistic 
      antitumor efficacy, which induced G1-phase cycle arrest and apoptosis. In 
      addition, rapamycin synergized with another ERKi, MEK162, and in turn, trametinib 
      synergized with other mTORi, Torin1 and OSI-027. Mechanistically, rapamycin in 
      combination with trametinib resulted in a greater decrease of phosphorylation of 
      AKT, ERK, mTOR and 4EBP1. In xenograft mouse model, co-administration of 
      rapamycin and trametinib caused a substantial suppression in tumor growth without 
      obvious drug toxicity. Overall, our study identifies a reasonable combined 
      strategy for treatment of NSCLC.
CI  - (c) The author(s).
FAU - Sun, Chao-Yue
AU  - Sun CY
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East 
      Road, Guangzhou, China 510060.
FAU - Li, Yi-Zhuo
AU  - Li YZ
AD  - Department of Medical Imaging, Sun Yat-Sen University Cancer Center, 651 Dongfeng 
      East Road, Guangzhou, China 510060.
FAU - Cao, Di
AU  - Cao D
AD  - Department of Medical Imaging, Sun Yat-Sen University Cancer Center, 651 Dongfeng 
      East Road, Guangzhou, China 510060.
FAU - Zhou, Yu-Feng
AU  - Zhou YF
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East 
      Road, Guangzhou, China 510060.
FAU - Zhang, Mei-Yin
AU  - Zhang MY
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East 
      Road, Guangzhou, China 510060.
FAU - Wang, Hui-Yun
AU  - Wang HY
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East 
      Road, Guangzhou, China 510060.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210725
PL  - Australia
TA  - Int J Biol Sci
JT  - International journal of biological sciences
JID - 101235568
RN  - 0 (Pyridones)
RN  - 0 (Pyrimidinones)
RN  - 33E86K87QN (trametinib)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - Lung Neoplasms/*drug therapy/metabolism/pathology
MH  - Mice, Inbred BALB C
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyridones/*administration & dosage
MH  - Pyrimidinones/*administration & dosage
MH  - Sirolimus/*administration & dosage
MH  - Xenograft Model Antitumor Assays
MH  - Mice
PMC - PMC8375233
OTO - NOTNLM
OT  - ERK
OT  - Lung cancer
OT  - Rapamycin
OT  - Synergy
OT  - Trametinib
OT  - mTOR
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2021/08/24 06:00
MHDA- 2022/03/19 06:00
PMCR- 2021/01/01
CRDT- 2021/08/23 06:23
PHST- 2021/05/14 00:00 [received]
PHST- 2021/07/11 00:00 [accepted]
PHST- 2021/08/23 06:23 [entrez]
PHST- 2021/08/24 06:00 [pubmed]
PHST- 2022/03/19 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - ijbsv17p3211 [pii]
AID - 10.7150/ijbs.62752 [doi]
PST - epublish
SO  - Int J Biol Sci. 2021 Jul 25;17(12):3211-3223. doi: 10.7150/ijbs.62752. 
      eCollection 2021.