PMID- 23653462
OWN - NLM
STAT- MEDLINE
DCOM- 20140124
LR  - 20220318
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Linking)
VI  - 20
IP  - 4
DP  - 2013 Aug
TI  - mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR 
      inhibitors in human bronchial carcinoids.
PG  - 463-75
LID - 10.1530/ERC-13-0042 [doi]
AB  - Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans 
      of medical treatment. Human BC primary cultures may display resistance to 
      everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of 
      cell viability reduction. Our aim was to assess whether the novel dual 
      phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in 
      everolimus-resistant human BC tissues and cell lines. In addition, we searched 
      for possible markers of the efficacy of mTOR inhibitors that may help in 
      identifying the patients who may benefit from treatment with mTOR inhibitors, 
      sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as 
      potent as everolimus in reducing cell viability and activating apoptosis in human 
      BC tissues that display sensitivity to mTOR inhibitors, but is not effective in 
      everolimus-resistant BC tissues and cell lines that bypass cyclin D1 
      downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed 
      in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. 
      In addition to total mTOR levels, putative markers of the sensitivity of BCs to 
      mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) 
      protein levels. Finally, we validated these markers in an independent BC group. 
      These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent 
      than everolimus in reducing the proliferation of human BC cells. 'Resistant' 
      cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that 
      these proteins may be useful as predictive markers of resistance to mTOR and 
      PI3K/mTOR inhibitors in human BCs.
FAU - Gagliano, Teresa
AU  - Gagliano T
AD  - Section of Endocrinology, Department of Medical Sciences, University of Ferrara, 
      Via Savonarola 9, Ferrara, Italy.
FAU - Bellio, Mariaenrica
AU  - Bellio M
FAU - Gentilin, Erica
AU  - Gentilin E
FAU - Mole, Daniela
AU  - Mole D
FAU - Tagliati, Federico
AU  - Tagliati F
FAU - Schiavon, Marco
AU  - Schiavon M
FAU - Cavallesco, Narciso Giorgio
AU  - Cavallesco NG
FAU - Andriolo, Luigi Gaetano
AU  - Andriolo LG
FAU - Ambrosio, Maria Rosaria
AU  - Ambrosio MR
FAU - Rea, Federico
AU  - Rea F
FAU - Degli Uberti, Ettore
AU  - Degli Uberti E
FAU - Zatelli, Maria Chiara
AU  - Zatelli MC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130624
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoid Tumor/drug therapy/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Drug Resistance, Neoplasm
MH  - Everolimus
MH  - Female
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Lung Neoplasms/drug therapy/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Quinolines/*pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - Young Adult
OTO - NOTNLM
OT  - bronchial carcinoids
OT  - mTOR inhibitors
OT  - mTOR resistance
OT  - predictive markers
EDAT- 2013/05/09 06:00
MHDA- 2014/01/25 06:00
CRDT- 2013/05/09 06:00
PHST- 2013/05/09 06:00 [entrez]
PHST- 2013/05/09 06:00 [pubmed]
PHST- 2014/01/25 06:00 [medline]
AID - ERC-13-0042 [pii]
AID - 10.1530/ERC-13-0042 [doi]
PST - epublish
SO  - Endocr Relat Cancer. 2013 Jun 24;20(4):463-75. doi: 10.1530/ERC-13-0042. Print 
      2013 Aug.