PMID- 18922904
OWN - NLM
STAT- MEDLINE
DCOM- 20081107
LR  - 20220309
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 20
DP  - 2008 Oct 15
TI  - Feedback mechanisms promote cooperativity for small molecule inhibitors of 
      epidermal and insulin-like growth factor receptors.
PG  - 8322-32
LID - 10.1158/0008-5472.CAN-07-6720 [doi]
AB  - Epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor 
      (IGF-IR) can cooperate to regulate tumor growth and survival, and synergistic 
      growth inhibition has been reported for combined blockade of EGFR and IGF-IR. 
      However, in preclinical models, only a subset of tumors exhibit high sensitivity 
      to this combination, highlighting the potential need for patient selection to 
      optimize clinical efficacy. Herein, we have characterized the molecular basis for 
      cooperative growth inhibition upon dual EGFR and IGF-IR blockade and provide 
      biomarkers that seem to differentiate response. We find for epithelial, but not 
      for mesenchymal-like, tumor cells that Akt is controlled cooperatively by EGFR 
      and IGF-IR. This correlates with synergistic apoptosis and growth inhibition in 
      vitro and growth regression in vivo upon combined blockade of both receptors. We 
      identified two molecular aspects contributing to synergy: (a) inhibition of EGFR 
      or IGF-IR individually promotes activation of the reciprocal receptor; (b) 
      inhibition of EGFR-directed mitogen-activated protein kinase (MAPK) shifts 
      regulation of Akt from EGFR toward IGF-IR. Targeting the MAPK pathway through 
      downstream MAPK/extracellular signal-regulated kinase kinase (MEK) antagonism 
      similarly promoted IGF-driven pAkt and synergism with IGF-IR inhibition. 
      Mechanistically, we find that inhibition of the MAPK pathway circumvents a 
      negative feedback loop imposed on the IGF-IR- insulin receptor substrate 1 
      (IRS-1) signaling complex, a molecular scenario that parallels the negative 
      feedback loop between mTOR-p70S6K and IRS-1 that mediates rapamycin-directed 
      IGF-IR signaling. Collectively, these data show that resistance to inhibition of 
      MEK, mTOR, and EGFR is associated with enhanced IGF-IR-directed Akt signaling, 
      where all affect feedback loops converging at the level of IRS-1.
FAU - Buck, Elizabeth
AU  - Buck E
AD  - Translational Research, Cancer Biology, OSI Pharmaceuticals, Farmingdale, New 
      York 11735., USA. ebuck@osip.com
FAU - Eyzaguirre, Alexandra
AU  - Eyzaguirre A
FAU - Rosenfeld-Franklin, Maryland
AU  - Rosenfeld-Franklin M
FAU - Thomson, Stuart
AU  - Thomson S
FAU - Mulvihill, Mark
AU  - Mulvihill M
FAU - Barr, Sharon
AU  - Barr S
FAU - Brown, Eric
AU  - Brown E
FAU - O'Connor, Mathew
AU  - O'Connor M
FAU - Yao, Yan
AU  - Yao Y
FAU - Pachter, Jonathan
AU  - Pachter J
FAU - Miglarese, Mark
AU  - Miglarese M
FAU - Epstein, David
AU  - Epstein D
FAU - Iwata, Kenneth K
AU  - Iwata KK
FAU - Haley, John D
AU  - Haley JD
FAU - Gibson, Neil W
AU  - Gibson NW
FAU - Ji, Qun-Sheng
AU  - Ji QS
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 
      (3-(3-(4-methylpiperazin-1-yl)cyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-8-ylamine)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (IRS1 protein, human)
RN  - 0 (Imidazoles)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 0 (Pyrazines)
RN  - 0 (Quinazolines)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/physiology
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - ErbB Receptors/*antagonists & inhibitors/physiology
MH  - Erlotinib Hydrochloride
MH  - Feedback, Physiological
MH  - Female
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - MAP Kinase Signaling System/drug effects
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasms, Experimental/drug therapy/pathology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/physiology
MH  - Pyrazines/*pharmacology
MH  - Quinazolines/*pharmacology
MH  - Receptor, IGF Type 1/*antagonists & inhibitors
MH  - Signal Transduction/drug effects
EDAT- 2008/10/17 09:00
MHDA- 2008/11/08 09:00
CRDT- 2008/10/17 09:00
PHST- 2008/10/17 09:00 [pubmed]
PHST- 2008/11/08 09:00 [medline]
PHST- 2008/10/17 09:00 [entrez]
AID - 68/20/8322 [pii]
AID - 10.1158/0008-5472.CAN-07-6720 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Oct 15;68(20):8322-32. doi: 10.1158/0008-5472.CAN-07-6720.