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High IGF-IR activity in triple-negative breast cancer cell lines and tumorgrafts correlates with sensitivity to anti-IGF-IR therapy.

AbstractPURPOSE:
We previously reported an insulin-like growth factor (IGF) gene expression signature, based on genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. We tested whether the IGF signature was affected by anti-IGF-I receptor (IGF-IR) inhibitors and whether the IGF signature correlated with response to a dual anti-IGF-IR/insulin receptor (InsR) inhibitor, BMS-754807.
EXPERIMENTAL DESIGN:
An IGF gene expression signature was examined in human breast tumors and cell lines and changes were noted following treatment of cell lines or xenografts with anti-IGF-IR antibodies or tyrosine kinase inhibitors. Sensitivity of cells to BMS-754807 was correlated with levels of the IGF signature. Human primary tumorgrafts were analyzed for the IGF signature and IGF-IR levels and activity, and MC1 tumorgrafts were treated with BMS-754807 and chemotherapy.
RESULTS:
The IGF gene expression signature was reversed in three different models (cancer cell lines or xenografts) treated with three different anti-IGF-IR therapies. The IGF signature was present in triple-negative breast cancers (TNBC) and TNBC cell lines, which were especially sensitive to BMS-754807, and sensitivity was significantly correlated to the expression of the IGF gene signature. The TNBC primary human tumorgraft MC1 showed high levels of both expression and activity of IGF-IR and IGF gene signature score. Treatment of MC1 with BMS-754807 showed growth inhibition and, in combination with docetaxel, tumor regression occurred until no tumor was palpable. Regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe.
CONCLUSIONS:
These studies provide a clear biological rationale to test anti-IGF-IR/InsR therapy in combination with chemotherapy in patients with TNBC.
AuthorsBeate C Litzenburger, Chad J Creighton, Anna Tsimelzon, Bonita T Chan, Susan G Hilsenbeck, Tao Wang, Joan M Carboni, Marco M Gottardis, Fei Huang, Jenny C Chang, Michael T Lewis, Mothaffar F Rimawi, Adrian V Lee
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 8 Pg. 2314-27 (Apr 15 2011) ISSN: 1557-3265 [Electronic] United States
PMID21177763 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright©2011 AACR.
Chemical References
  • BMS 754807
  • Pyrazoles
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Taxoids
  • Triazines
  • Docetaxel
  • Insulin-Like Growth Factor I
  • Receptor, ErbB-2
  • Receptor, IGF Type 1
  • Receptor, Insulin
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Apoptosis (drug effects)
  • Breast Neoplasms (drug therapy, genetics, metabolism)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cluster Analysis
  • Docetaxel
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Immunoblotting
  • Insulin-Like Growth Factor I (metabolism, pharmacology)
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • NIH 3T3 Cells
  • Pyrazoles (administration & dosage, pharmacology)
  • Receptor, ErbB-2 (metabolism)
  • Receptor, IGF Type 1 (antagonists & inhibitors, genetics, metabolism)
  • Receptor, Insulin (antagonists & inhibitors, genetics, metabolism)
  • Receptors, Estrogen (metabolism)
  • Receptors, Progesterone (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Taxoids (administration & dosage, pharmacology)
  • Triazines (administration & dosage, pharmacology)
  • Xenograft Model Antitumor Assays

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