PMID- 21980128
OWN - NLM
STAT- MEDLINE
DCOM- 20120511
LR  - 20211203
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 10
IP  - 12
DP  - 2011 Dec
TI  - Akt/mTOR counteract the antitumor activities of cixutumumab, an anti-insulin-like 
      growth factor I receptor monoclonal antibody.
PG  - 2437-48
LID - 10.1158/1535-7163.MCT-11-0235 [doi]
AB  - Recent reports have shown limited anticancer therapeutic efficacy of insulin-like 
      growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb), but the 
      resistance mechanisms have not been completely identified. Because cooperation 
      between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance 
      to inhibitors of individual receptor tyrosine kinases, we investigated the 
      involvement of EGFR signaling in resistance to IGF-1R mAb and the underlying 
      mechanisms of action. Most head and neck squamous cell carcinoma (HNSCC) tissues 
      had coexpression of total and phosphorylated IGF-1R and EGFR at high levels 
      compared with paired adjacent normal tissues. Treatment with cixutumumab 
      (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mTOR, 
      resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and 
      activation of the EGFR pathway in cixutumumab-resistant HNSCC and non-small cell 
      lung cancer (NSCLC) cells. Targeting mTOR and EGFR pathways by treatment with 
      rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented 
      cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic 
      antitumor effects in vitro and in vivo. These data show that resistance to IGF-1R 
      inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of 
      EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective 
      targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC.
FAU - Shin, Dong Hoon
AU  - Shin DH
AD  - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA.
FAU - Min, Hye-Young
AU  - Min HY
FAU - El-Naggar, Adel K
AU  - El-Naggar AK
FAU - Lippman, Scott M
AU  - Lippman SM
FAU - Glisson, Bonnie
AU  - Glisson B
FAU - Lee, Ho-Young
AU  - Lee HY
LA  - eng
GR  - P50 CA097007-10/CA/NCI NIH HHS/United States
GR  - P50 CA097007/CA/NCI NIH HHS/United States
GR  - R01 CA100816/CA/NCI NIH HHS/United States
GR  - R01 CA100816-08/CA/NCI NIH HHS/United States
GR  - P30 CA023100/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111006
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 2285XW22DR (cixutumumab)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism
MH  - Carcinoma, Squamous Cell/drug therapy/genetics/metabolism
MH  - Drug Antagonism
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Head and Neck Neoplasms/drug therapy/genetics/metabolism
MH  - Humans
MH  - Lung Neoplasms/drug therapy/genetics/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism/*physiology
MH  - Receptor, IGF Type 1/antagonists & inhibitors/immunology
MH  - Squamous Cell Carcinoma of Head and Neck
MH  - TOR Serine-Threonine Kinases/genetics/metabolism/*physiology
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
PMC - PMC3237768
MID - NIHMS329998
COIS- Conflicts of Interest: The authors declare no conflict of interest.
EDAT- 2011/10/08 06:00
MHDA- 2012/05/12 06:00
PMCR- 2012/12/01
CRDT- 2011/10/08 06:00
PHST- 2011/10/08 06:00 [entrez]
PHST- 2011/10/08 06:00 [pubmed]
PHST- 2012/05/12 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - 1535-7163.MCT-11-0235 [pii]
AID - 10.1158/1535-7163.MCT-11-0235 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2011 Dec;10(12):2437-48. doi: 10.1158/1535-7163.MCT-11-0235. 
      Epub 2011 Oct 6.