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

Beate 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

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Purpose: 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 triplenegative 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.

Original languageEnglish (US)
Pages (from-to)2314-2327
Number of pages14
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
StatePublished - Apr 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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