Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis

Elisa Benedettini, Lynette M. Sholl, Michael Peyton, John Reilly, Christopher Ware, Lenora Davis, Natalie Vena, Dyane Bailey, Beow Y. Yeap, Michelangelo Fiorentino, Azra H. Ligon, Bo Sheng Pan, Victoria Richon, John D. Minna, Adi F. Gazdar, Giulio Draetta, Silvano Bosari, Lucian R. Chirieac, Bart Lutterbach, Massimo Loda

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Abstract

Most non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitor (TKI) therapy. However, about 30% exhibit primary resistance to EGFR TKI therapy. Here we report that Met protein expression and phosphorylation were associated with primary resistance to EGFR TKI therapy in NSCLC patients harboring EGFR mutations, implicating Met as a de novo mechanism of resistance. In a separate patient cohort, Met expression and phosphorylation were also associated with development of NSCLC brain metastasis and were selectively enriched in brain metastases relative to paired primary lung tumors. A similar metastasis-specific activation of Met occurred in vitro in the isogenous cell lines H2073 and H1993, which are derived from the primary lung tumor and a metastasis, respectively, from the same patient. We conclude that Met activation is found in NSCLC before EGFR-targeted therapy and is associated with both primary resistance to EGFR inhibitor therapy and with the development of metastases. If confirmed in larger cohorts, our analysis suggests that patient tumors harboring both Met activation and EGFR mutation could potentially benefit from early intervention with a combination of EGFR and Met inhibitors.

Original languageEnglish (US)
Pages (from-to)415-423
Number of pages9
JournalAmerican Journal of Pathology
Volume177
Issue number1
DOIs
StatePublished - Jul 2010

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Neoplasm Metastasis
Brain
Protein-Tyrosine Kinases
Mutation
Phosphorylation
Therapeutics
Neoplasms
Lung
Brain Neoplasms
Cohort Studies
Cell Line
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. / Benedettini, Elisa; Sholl, Lynette M.; Peyton, Michael; Reilly, John; Ware, Christopher; Davis, Lenora; Vena, Natalie; Bailey, Dyane; Yeap, Beow Y.; Fiorentino, Michelangelo; Ligon, Azra H.; Pan, Bo Sheng; Richon, Victoria; Minna, John D.; Gazdar, Adi F.; Draetta, Giulio; Bosari, Silvano; Chirieac, Lucian R.; Lutterbach, Bart; Loda, Massimo.

In: American Journal of Pathology, Vol. 177, No. 1, 07.2010, p. 415-423.

Research output: Contribution to journalArticle

Benedettini, E, Sholl, LM, Peyton, M, Reilly, J, Ware, C, Davis, L, Vena, N, Bailey, D, Yeap, BY, Fiorentino, M, Ligon, AH, Pan, BS, Richon, V, Minna, JD, Gazdar, AF, Draetta, G, Bosari, S, Chirieac, LR, Lutterbach, B & Loda, M 2010, 'Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis', American Journal of Pathology, vol. 177, no. 1, pp. 415-423. https://doi.org/10.2353/ajpath.2010.090863
Benedettini, Elisa ; Sholl, Lynette M. ; Peyton, Michael ; Reilly, John ; Ware, Christopher ; Davis, Lenora ; Vena, Natalie ; Bailey, Dyane ; Yeap, Beow Y. ; Fiorentino, Michelangelo ; Ligon, Azra H. ; Pan, Bo Sheng ; Richon, Victoria ; Minna, John D. ; Gazdar, Adi F. ; Draetta, Giulio ; Bosari, Silvano ; Chirieac, Lucian R. ; Lutterbach, Bart ; Loda, Massimo. / Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. In: American Journal of Pathology. 2010 ; Vol. 177, No. 1. pp. 415-423.
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AU - Richon, Victoria

AU - Minna, John D.

AU - Gazdar, Adi F.

AU - Draetta, Giulio

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AU - Loda, Massimo

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