PMID- 19723757
OWN - NLM
STAT- MEDLINE
DCOM- 20091020
LR  - 20211020
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 94
IP  - 10
DP  - 2009 Oct
TI  - Dual inhibition of mitogen-activated protein kinase kinase and mammalian target 
      of rapamycin in differentiated and anaplastic thyroid cancer.
PG  - 4107-12
LID - 10.1210/jc.2009-0662 [doi]
AB  - CONTEXT: Differentiated thyroid cancer and anaplastic thyroid cancer tumors 
      frequently have activation of the ras/raf /MAPK kinase (MEK)/ERK and 
      phosphatidylinositol 3-kinase (PI-3K)/AKT/mammalian target of rapamycin (mTOR) 
      signaling pathways. OBJECTIVE: The objective of the study was to investigate the 
      efficacy of MEK and mTOR inhibitors in preclinical thyroid cancer treatment 
      models with defined mutation status. EXPERIMENTAL DESIGN: The MEK inhibitor 
      AZD6244 (ARRY-142886) and mTOR inhibitor rapamycin were tested separately and in 
      combination in 10 differentiated thyroid cancer and anaplastic thyroid cancer 
      cell lines and in a xenograft model for evidence of pathway inhibition, growth 
      inhibition, apoptosis, and long-range adaptation and resistance. RESULTS: Seven 
      of 10 tested lines had evidence of significant basal activity of the 
      PI-3K/AKT/mTOR pathway, with elevated phosphorylated AKT and phosphorylated p70 
      S6 kinase. Activation of ras/RAF/MEK/ERK was equally common in this panel. All 10 
      lines exhibited better than 60% growth inhibition with combined MEK and mTOR 
      inhibition, including lines with BRAF, Ret-PTC, ras, and PTEN mutations. 
      Rapamycin or AZD6244 alone achieved this threshold in six and two lines, 
      respectively. Dual-pathway inhibition in the Ret-PTC mutant cell line TPC1 caused 
      an intense G(1) arrest in cell culture and reversible cytostatic inhibition in a 
      xenograft model. We did not observe significant feedback up-regulation of AKT 
      activation in either acute or prolonged exposures. CONCLUSION: These preclinical 
      results support the inclusion of thyroid cancer patients in early-phase clinical 
      trials combining RAS/RAF/MEK/ERK and PI-3K/AKT/mTOR pathway inhibition.
FAU - Jin, Ning
AU  - Jin N
AD  - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins 
      University School of Medicine, Baltimore, Maryland 21231-1000, USA.
FAU - Jiang, Tianyun
AU  - Jiang T
FAU - Rosen, D Marc
AU  - Rosen DM
FAU - Nelkin, Barry D
AU  - Nelkin BD
FAU - Ball, Douglas W
AU  - Ball DW
LA  - eng
GR  - P50 CA096784/CA/NCI NIH HHS/United States
GR  - CA-96784/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090901
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (AZD 6244)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Benzimidazoles)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology
MH  - Apoptosis/drug effects
MH  - Benzimidazoles/*pharmacology
MH  - Blotting, Western
MH  - Carcinoma/*drug therapy/*enzymology
MH  - Cell Line, Tumor
MH  - Flow Cytometry
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Mice
MH  - Mice, Nude
MH  - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - Thyroid Neoplasms/*drug therapy/*enzymology
MH  - Transplantation, Heterologous
PMC - PMC2758734
EDAT- 2009/09/03 06:00
MHDA- 2009/10/21 06:00
PMCR- 2010/10/01
CRDT- 2009/09/03 09:00
PHST- 2009/09/03 09:00 [entrez]
PHST- 2009/09/03 06:00 [pubmed]
PHST- 2009/10/21 06:00 [medline]
PHST- 2010/10/01 00:00 [pmc-release]
AID - jc.2009-0662 [pii]
AID - 6810 [pii]
AID - 10.1210/jc.2009-0662 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2009 Oct;94(10):4107-12. doi: 10.1210/jc.2009-0662. Epub 
      2009 Sep 1.