PMID- 28675026
OWN - NLM
STAT- MEDLINE
DCOM- 20180904
LR  - 20231112
IS  - 2005-9256 (Electronic)
IS  - 1598-2998 (Print)
IS  - 1598-2998 (Linking)
VI  - 50
IP  - 2
DP  - 2018 Apr
TI  - Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation 
      of Anaplastic Lymphoma Kinase‒Positive Anaplastic Large Cell Lymphoma.
PG  - 599-613
LID - 10.4143/crt.2016.357 [doi]
AB  - PURPOSE: Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin 
      lymphoma, of which over 50% of cases have an aberrant nucleophosmin 
      (NPM)‒anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of 
      rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown 
      promising antitumor activity in ALK-positive cancer cell lines. However, their 
      combined effect has not yet been investigated. MATERIALS AND METHODS: We 
      evaluated the anti-proliferative effects of everolimus and/or crizotinib in 
      ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma 
      cell line, NCI-H2228. RESULTS: We found that individually, both everolimus and 
      crizotinib potently inhibited cell growth in a dose-dependent manner in both 
      Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically 
      inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant 
      AKT and ERK phosphorylation induced by everolimus. Combination treatment also 
      significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis 
      compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the 
      Karpas 299 xenograft model, the combination treatment exerted a stronger 
      antitumor effect than monotherapies, without significant change in body weight. 
      The synergistic effect of everolimus and crizotinib was also reproduced in the 
      ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment 
      abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little 
      effect on the Ras/ERK pathway in NCI-H2228 cells. CONCLUSION: Crizotinib 
      combinedwith everolimus synergistically inhibits proliferation of ALK-positive 
      ALCL cells. Our results suggest that this novel combination is worthy of further 
      clinical development in patients with ALK-positive ALCL.
FAU - Xu, Wendan
AU  - Xu W
AD  - Cancer Research Institute, Seoul National University, Seoul, Korea.
FAU - Kim, Ji-Won
AU  - Kim JW
AD  - Cancer Research Institute, Seoul National University, Seoul, Korea.
AD  - Department of Internal Medicine, Seoul National University Bundang Hospital, 
      Seongnam, Korea.
FAU - Jung, Woo June
AU  - Jung WJ
AD  - Cancer Research Institute, Seoul National University, Seoul, Korea.
FAU - Koh, Youngil
AU  - Koh Y
AD  - Cancer Research Institute, Seoul National University, Seoul, Korea.
AD  - Department of Internal Medicine, Seoul National University Hospital, Seoul, 
      Korea.
AD  - Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
FAU - Yoon, Sung-Soo
AU  - Yoon SS
AD  - Cancer Research Institute, Seoul National University, Seoul, Korea.
AD  - Department of Internal Medicine, Seoul National University Hospital, Seoul, 
      Korea.
AD  - Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
LA  - eng
PT  - Journal Article
DEP - 20170619
PL  - Korea (South)
TA  - Cancer Res Treat
JT  - Cancer research and treatment
JID - 101155137
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridines)
RN  - 53AH36668S (Crizotinib)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Alk protein, mouse)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Anaplastic Lymphoma Kinase
MH  - Animals
MH  - Crizotinib
MH  - Drug Synergism
MH  - Everolimus/pharmacology/*therapeutic use
MH  - Humans
MH  - Immunohistochemistry
MH  - Lymphoma, Large-Cell, Anaplastic/*drug therapy/pathology
MH  - Mice
MH  - Protein Kinase Inhibitors/pharmacology/*therapeutic use
MH  - Pyrazoles/pharmacology/*therapeutic use
MH  - Pyridines/pharmacology/*therapeutic use
MH  - Receptor Protein-Tyrosine Kinases/*drug effects
PMC - PMC5912135
OTO - NOTNLM
OT  - Anaplastic large cell lymphoma
OT  - Anaplastic lymphoma kinase
OT  - Crizotinib
OT  - Everolimus
OT  - TOR serine-threonine kinases
COIS- Conflict of interest relevant to this article was not reported.
EDAT- 2017/07/05 06:00
MHDA- 2018/09/05 06:00
PMCR- 2018/04/01
CRDT- 2017/07/05 06:00
PHST- 2016/08/08 00:00 [received]
PHST- 2017/06/10 00:00 [accepted]
PHST- 2017/07/05 06:00 [pubmed]
PHST- 2018/09/05 06:00 [medline]
PHST- 2017/07/05 06:00 [entrez]
PHST- 2018/04/01 00:00 [pmc-release]
AID - crt.2016.357 [pii]
AID - crt-2016-357 [pii]
AID - 10.4143/crt.2016.357 [doi]
PST - ppublish
SO  - Cancer Res Treat. 2018 Apr;50(2):599-613. doi: 10.4143/crt.2016.357. Epub 2017 
      Jun 19.