PMID- 20457905
OWN - NLM
STAT- MEDLINE
DCOM- 20100714
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 24
DP  - 2010 Jun 15
TI  - Insulin receptor functionally enhances multistage tumor progression and conveys 
      intrinsic resistance to IGF-1R targeted therapy.
PG  - 10791-8
LID - 10.1073/pnas.0914076107 [doi]
AB  - The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an 
      important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of 
      IGF-1R signaling are currently being tested in clinical cancer trials aiming to 
      assess the utility of this receptor as a therapeutic target. Despite mounting 
      evidence that the highly homologous insulin receptor (IR) can also convey 
      protumorigenic signals, its direct role in cancer progression has not been 
      genetically defined in vivo, and it remains unclear whether such a role for IR 
      signaling could compromise the efficacy of selective IGF-1R targeting strategies. 
      A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the 
      IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated 
      malignant progression upon IGF-1R overexpression. Surprisingly, preclinical 
      trials with an inhibitory monoclonal antibody to IGF-1R did not significantly 
      impact tumor growth, prompting us to investigate the involvement of IR. The 
      levels of IR were found to be significantly up-regulated during multistep 
      progression from hyperplastic lesions to islet tumors. Its functional involvement 
      was revealed by genetic disruption of the IR gene in the oncogene-expressing 
      pancreatic beta cells, which resulted in reduced tumor burden accompanied by 
      increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to 
      anti-IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed 
      resistance to IGF-1R inhibition in human breast cancer cells. The results predict 
      that elevated IR signaling before and after treatment will respectively manifest 
      intrinsic and adaptive resistance to anti-IGF-1R therapies.
FAU - Ulanet, Danielle B
AU  - Ulanet DB
AD  - Department of Biochemistry and Biophysics, Diabetes Center, University of 
      California, San Francisco, CA 94143, USA.
FAU - Ludwig, Dale L
AU  - Ludwig DL
FAU - Kahn, C Ronald
AU  - Kahn CR
FAU - Hanahan, Douglas
AU  - Hanahan D
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100510
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Receptor, IGF Type 2)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
CIN - Nat Rev Cancer. 2010 Jul;10(7):453. doi: 10.1038/nrc2883. PMID: 20589970
CIN - Nat Rev Drug Discov. 2010 Jul;9(7):518. doi: 10.1038/nrd3211. PMID: 20592746
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology
MH  - Breast Neoplasms/metabolism/therapy
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Neoplasms, Experimental/*metabolism/*therapy
MH  - Neuroendocrine Tumors/metabolism/therapy
MH  - Pancreatic Neoplasms/metabolism/therapy
MH  - Receptor, IGF Type 1/*antagonists & inhibitors
MH  - Receptor, IGF Type 2/metabolism
MH  - Receptor, Insulin/deficiency/genetics/*metabolism
MH  - Signal Transduction
PMC - PMC2890766
COIS- Conflict of interest statement: D.L.L. is an employee of ImClone. However, this 
      study does not promote the ImClone drug A12.
EDAT- 2010/05/12 06:00
MHDA- 2010/07/16 06:00
PMCR- 2010/05/10
CRDT- 2010/05/12 06:00
PHST- 2010/05/12 06:00 [entrez]
PHST- 2010/05/12 06:00 [pubmed]
PHST- 2010/07/16 06:00 [medline]
PHST- 2010/05/10 00:00 [pmc-release]
AID - 0914076107 [pii]
AID - 200914076 [pii]
AID - 10.1073/pnas.0914076107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10791-8. doi: 
      10.1073/pnas.0914076107. Epub 2010 May 10.