PMID- 21258412
OWN - NLM
STAT- MEDLINE
DCOM- 20110722
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 30
IP  - 20
DP  - 2011 May 19
TI  - The long and winding road to rational treatment of cancer associated with 
      LKB1/AMPK/TSC/mTORC1 signaling.
PG  - 2289-303
LID - 10.1038/onc.2010.630 [doi]
AB  - The liver kinase B1 (LKB1)/adenosine mono-phosphate-activated protein kinase 
      (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) 
      complex (mTORC1) cassette constitutes a canonical signaling pathway that 
      integrates information on the metabolic and nutrient status and translates this 
      into regulation of cell growth. Alterations in this pathway are associated with a 
      wide variety of cancers and hereditary hamartoma syndromes, diseases in which 
      hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have 
      been developed for clinical use, and these drugs have been anticipated to provide 
      efficient treatment for these diseases. In the present review, we provide an 
      overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant 
      signaling associates with cancer development, and indicate the difficulties 
      encountered when biochemical data are extrapolated to provide avenues for 
      rational treatment of disease when targeting this signaling pathway. A careful 
      examination of preclinical and clinical studies performed with rapamycin or 
      derivatives thereof shows that although results are encouraging, we are only half 
      way in the long and winding road to design rationale treatment targeted at the 
      LKB1/AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this 
      pathway such as the Peutz-Jeghers syndrome and TSC, provide perfect models to 
      study the relationship between genetics and disease phenotype, and to delineate 
      the complexities that underlie translation of biochemical and genetical 
      information to clinical management, and thus provide important clues for devising 
      novel rational medicine for cancerous diseases in general.
FAU - van Veelen, W
AU  - van Veelen W
AD  - Department of Gastroenterology and Hepatology, Erasmus Medical University Center, 
      Rotterdam, The Netherlands.
FAU - Korsse, S E
AU  - Korsse SE
FAU - van de Laar, L
AU  - van de Laar L
FAU - Peppelenbosch, M P
AU  - Peppelenbosch MP
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20110124
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antibiotics, Antineoplastic)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Antibiotics, Antineoplastic/therapeutic use
MH  - Humans
MH  - Molecular Targeted Therapy
MH  - Neoplasms/*drug therapy/*metabolism
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - *Signal Transduction
MH  - Sirolimus/therapeutic use
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tuberous Sclerosis/*metabolism
EDAT- 2011/01/25 06:00
MHDA- 2011/07/23 06:00
CRDT- 2011/01/25 06:00
PHST- 2011/01/25 06:00 [entrez]
PHST- 2011/01/25 06:00 [pubmed]
PHST- 2011/07/23 06:00 [medline]
AID - onc2010630 [pii]
AID - 10.1038/onc.2010.630 [doi]
PST - ppublish
SO  - Oncogene. 2011 May 19;30(20):2289-303. doi: 10.1038/onc.2010.630. Epub 2011 Jan 
      24.