MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients.
BACKGROUND
MET amplification has been detected in approximately 20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy.


METHODS
We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents.


RESULTS
HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line.


CONCLUSIONS
MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.
Cappuzzo
F
F
Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy. federico.cappuzzo@humanitas.it
Jänne
P A
PA
Skokan
M
M
Finocchiaro
G
G
Rossi
E
E
Ligorio
C
C
Zucali
P A
PA
Terracciano
L
L
Toschi
L
L
Roncalli
M
M
Destro
A
A
Incarbone
M
M
Alloisio
M
M
Santoro
A
A
Varella-Garcia
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1 / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines / Q000627:therapeutic use*; D017978:Receptors, Growth Factor / Q000235:genetics*; D016019:Survival Analysis
D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib