PMID- 17047074
OWN - NLM
STAT- MEDLINE
DCOM- 20061204
LR  - 20220321
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 20
DP  - 2006 Oct 15
TI  - Heterodimerization of insulin-like growth factor receptor/epidermal growth factor 
      receptor and induction of survivin expression counteract the antitumor action of 
      erlotinib.
PG  - 10100-11
AB  - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have 
      been used to treat non-small cell lung cancer (NSCLC). However, the overall 
      response rate to EGFR TKIs is limited, and the mechanisms mediating resistance to 
      the drugs are poorly understood. Here, we report that insulin-like growth 
      factor-I receptor (IGF-IR) activation interferes with the antitumor activity of 
      erlotinib, an EGFR TKI. Treatment with erlotinib increased the levels of 
      EGFR/IGF-IR heterodimer localized on cell membrane, activated IGF-IR and its 
      downstream signaling mediators, and stimulated mammalian target of rapamycin 
      (mTOR)-mediated de novo protein synthesis of EGFR and survivin in NSCLC cells. 
      Inhibition of IGF-IR activation, suppression of mTOR-mediated protein synthesis, 
      or knockdown of survivin expression abolished resistance to erlotinib and induced 
      apoptosis in NSCLC cells in vitro and in vivo. Our data suggest that enhanced 
      synthesis of survivin protein mediated by the IGFR/EGFR heterodimer counteracts 
      the antitumor action of erlotinib, indicating the needs of integration of 
      IGF-IR-targeted agents to the treatment regimens with EGFR TKI for patients with 
      lung cancer.
FAU - Morgillo, Floriana
AU  - Morgillo F
AD  - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas 
      M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
FAU - Woo, Jong Kyu
AU  - Woo JK
FAU - Kim, Edward S
AU  - Kim ES
FAU - Hong, Waun Ki
AU  - Hong WK
FAU - Lee, Ho-Young
AU  - Lee HY
LA  - eng
GR  - R01 CA100816/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (BIRC5 protein, human)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Somatomedin)
RN  - 0 (Survivin)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Membrane/metabolism
MH  - Dimerization
MH  - Drug Resistance, Neoplasm
MH  - ErbB Receptors/biosynthesis/genetics/*metabolism
MH  - Erlotinib Hydrochloride
MH  - Female
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins
MH  - Lung Neoplasms/*drug therapy/metabolism/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Microtubule-Associated Proteins/*biosynthesis/genetics
MH  - Neoplasm Proteins/*biosynthesis/genetics
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Kinases/metabolism
MH  - Quinazolines/*pharmacology
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Receptors, Somatomedin/*metabolism
MH  - Signal Transduction
MH  - Survivin
MH  - TOR Serine-Threonine Kinases
MH  - Xenograft Model Antitumor Assays
EDAT- 2006/10/19 09:00
MHDA- 2006/12/09 09:00
CRDT- 2006/10/19 09:00
PHST- 2006/10/19 09:00 [pubmed]
PHST- 2006/12/09 09:00 [medline]
PHST- 2006/10/19 09:00 [entrez]
AID - 66/20/10100 [pii]
AID - 10.1158/0008-5472.CAN-06-1684 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Oct 15;66(20):10100-11. doi: 10.1158/0008-5472.CAN-06-1684.