Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition

Antonio Gualberto, Marisa Dolled-Filhart, Mark Gustavson, Jason Christiansen, Yu Fen Wang, Mary L. Hixon, Jennifer Reynolds, Sandra McDonald, Agnes Ang, David L. Rimm, Corey J. Langer, Johnetta Blakely, Linda Garland, Luis G. Paz-Ares, Daniel D. Karp, Adrian V. Lee

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Purpose: This study aimed to identify molecular determinants of sensitivity of non-small cell lung cancer (NSCLC) to anti-insulin-like growth factor receptor (IGF-IR) therapy. Experimental Design: A total of 216 tumor samples were investigated, of which 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase II study of figitumumab, a monoclonal antibody against IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, epidermal growth factor receptor, IGF-II, IGF-IIR, insulin receptor substrate 1 (IRS-1), IRS-2, vimentin, and E-cadherin. Subcellular localization of IRS-1 and phosphorylation levels of mitogen-activated protein kinase and Akt1 were also analyzed. Results: IGF-IR was differentially expressed across histologic subtypes (P = 0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with figitumumab (P = 0.008). Because no other biomarker/response interaction was observed using classical histologic subtyping, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified three NSCLC subsets that resembled the steps of the epithelial to mesenchymal transition: E-cadherin high/IRS-1 low (epithelial-like), E-cadherin intermediate/IRS-1 high (transitional), and E-cadherin low/IRS-1 low (mesenchymal-like). Several markers of the IGF-IR pathway were overexpressed in the transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and figitumumab was observed in transitional tumors (71%) compared with those in themesenchymal-like subset (32%; P = 0.03).Only one epithelial-like tumorwas identified in the phase II study, suggesting that advanced NSCLC has undergone significant dedifferentiation at diagnosis. Conclusion: NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition.

Original languageEnglish (US)
Pages (from-to)4654-4665
Number of pages12
JournalClinical Cancer Research
Volume16
Issue number18
DOIs
StatePublished - Sep 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition'. Together they form a unique fingerprint.

  • Cite this

    Gualberto, A., Dolled-Filhart, M., Gustavson, M., Christiansen, J., Wang, Y. F., Hixon, M. L., Reynolds, J., McDonald, S., Ang, A., Rimm, D. L., Langer, C. J., Blakely, J., Garland, L., Paz-Ares, L. G., Karp, D. D., & Lee, A. V. (2010). Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition. Clinical Cancer Research, 16(18), 4654-4665. https://doi.org/10.1158/1078-0432.CCR-10-0089