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 L Garland, Luis G. Paz-Ares, Daniel D. Karp, Adrian V. Lee

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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

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IGF Type 1 Receptor
Insulin Receptor Substrate Proteins
Non-Small Cell Lung Carcinoma
Cadherins
Neoplasms
Biomarkers
Epithelial Cells
Somatomedin Receptors
Insulin-Like Growth Factor II
Epithelial-Mesenchymal Transition
Vimentin
Mitogen-Activated Protein Kinases
Principal Component Analysis
Combination Drug Therapy
Epidermal Growth Factor Receptor
Cluster Analysis
Research Design
Monoclonal Antibodies
Phosphorylation
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition. / Gualberto, Antonio; Dolled-Filhart, Marisa; Gustavson, Mark; Christiansen, Jason; Wang, Yu Fen; Hixon, Mary L.; Reynolds, Jennifer; McDonald, Sandra; Ang, Agnes; Rimm, David L.; Langer, Corey J.; Blakely, Johnetta; Garland, Linda L; Paz-Ares, Luis G.; Karp, Daniel D.; Lee, Adrian V.

In: Clinical Cancer Research, Vol. 16, No. 18, 15.09.2010, p. 4654-4665.

Research output: Contribution to journalArticle

Gualberto, A, Dolled-Filhart, M, Gustavson, M, Christiansen, J, Wang, YF, Hixon, ML, Reynolds, J, McDonald, S, Ang, A, Rimm, DL, Langer, CJ, Blakely, J, Garland, LL, Paz-Ares, LG, Karp, DD & Lee, AV 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, vol. 16, no. 18, pp. 4654-4665. https://doi.org/10.1158/1078-0432.CCR-10-0089
Gualberto, Antonio ; Dolled-Filhart, Marisa ; Gustavson, Mark ; Christiansen, Jason ; Wang, Yu Fen ; Hixon, Mary L. ; Reynolds, Jennifer ; McDonald, Sandra ; Ang, Agnes ; Rimm, David L. ; Langer, Corey J. ; Blakely, Johnetta ; Garland, Linda L ; Paz-Ares, Luis G. ; Karp, Daniel D. ; Lee, Adrian V. / Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 18. pp. 4654-4665.
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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.",
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AU - Gualberto, Antonio

AU - Dolled-Filhart, Marisa

AU - Gustavson, Mark

AU - Christiansen, Jason

AU - Wang, Yu Fen

AU - Hixon, Mary L.

AU - Reynolds, Jennifer

AU - McDonald, Sandra

AU - Ang, Agnes

AU - Rimm, David L.

AU - Langer, Corey J.

AU - Blakely, Johnetta

AU - Garland, Linda L

AU - Paz-Ares, Luis G.

AU - Karp, Daniel D.

AU - Lee, Adrian V.

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N2 - 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.

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