Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis.
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.
Benedettini
Elisa
E
Department of Medical Oncology, the Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston Massachusetts, USA.
Sholl
Lynette M
LM
Peyton
Michael
M
Reilly
John
J
Ware
Christopher
C
Davis
Lenora
L
Vena
Natalie
N
Bailey
Dyane
D
Yeap
Beow Y
BY
Fiorentino
Michelangelo
M
Ligon
Azra H
AH
Pan
Bo-Sheng
BS
Richon
Victoria
V
Minna
John D
JD
Gazdar
Adi F
AF
Draetta
Giulio
G
Bosari
Silvano
S
Chirieac
Lucian R
LR
Lutterbach
Bart
B
Loda
Massimo
M
D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met