Intrinsic resistance to cixutumumab is conferred by distinct isoforms of the insulin receptor

Amelie Forest, Michael Amatulli, Dale L. Ludwig, Christopher B. Damoci, Ying Wang, Colleen A. Burns, Gregory P. Donoho, Nina Zanella, Heinz H. Fiebig, Marie C. Prewett, David Surguladze, James T. DeLigio, Peter J. Houghton, Malcolm A. Smith, Ruslan Novosiadly

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Despite a recent shift away from anti-insulin-like growth factor I receptor (IGF-IR) therapy, this target has been identified as a key player in the resistance mechanisms to various conventional and targeted agents, emphasizing its value as a therapy, provided that it is used in the right patient population. Molecular markers predictive of antitumor activity of IGF-IR inhibitors remain largely unidentified. The aim of this study is to evaluate the impact of insulin receptor (IR) isoforms on the antitumor efficacy of cixutumumab, a humanized mAb against IGF-IR, and to correlate their expression with therapeutic outcome. The data demonstrate that expression of total IR rather than individual IR isoforms inversely correlates with single-Agent cixutumumab efficacy in pediatric solid tumor models in vivo. Total IR, IR-A, and IR-B expression adversely affects the outcome of cixutumumab in combination with chemotherapy in patient-derived xenograft models of lung adenocarcinoma. IR-A overexpression in tumor cells confers complete resistance to cixutumumab in vitro and in vivo, whereas IR-B results in a partial resistance. Resistance in IRB- overexpressing cells is fully reversed by anti-IGF-II antibodies, suggesting that IGF-II is a driver of cixutumumab resistance in this setting. The present study links IR isoforms, IGF-II, and cixutumumab efficacy mechanistically and identifies total IR as a biomarker predictive of intrinsic resistance to anti-IGF-IR antibody. Implications: This study identifies total IRasabiomarker predictive of primary resistance to IGF-IR antibodies and provides a rationale for new clinical trials enriched for patients whose tumors display low IR expression.

Original languageEnglish (US)
Pages (from-to)1615-1626
Number of pages12
JournalMolecular Cancer Research
Volume13
Issue number12
DOIs
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Forest, A., Amatulli, M., Ludwig, D. L., Damoci, C. B., Wang, Y., Burns, C. A., Donoho, G. P., Zanella, N., Fiebig, H. H., Prewett, M. C., Surguladze, D., DeLigio, J. T., Houghton, P. J., Smith, M. A., & Novosiadly, R. (2015). Intrinsic resistance to cixutumumab is conferred by distinct isoforms of the insulin receptor. Molecular Cancer Research, 13(12), 1615-1626. https://doi.org/10.1158/1541-7786.MCR-15-0279