Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status.
BACKGROUND
Some types of somatic mutation of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). However, most of the patients with this type of sensitive mutations in their tumor show acquired resistance during the TKI treatment.


METHODS
The mutations in exons 19-21 of the EGFR gene were examined in both the pre-treatment and the post-treatment gefitinib resistant tumors in 10 patients with lung adenocarcinoma. Eight patients were recurrent cases after surgery, and two patients were non-surgical cases whose tumor specimens were obtained from the metastatic lymph node and endobronchially invading tumor.


RESULTS
In 10 patients, 5 patients had a deletion in exon 19 and another 5 did L858R mutation in exon 21 of EGFR in gefitinib pre-treatment tumors. The mutation status did not change in the gefitinib-resistant tumors. In 7 of 10 patients, the gefitinib-resistant tumors had a secondary T790M mutation, which was not detected in the gefitinib pre-treatment tumors. In one patient, only one of the 4 gefitinib-resistant tumors showed the T790M mutation. Neither other novel secondary mutations of EGFR nor the K-ras were observed in their gefitinib-resistant tumors. Neither MET gene amplification nor HGF were observed in their gefitinib-resistant tumors without T790M mutation.


CONCLUSIONS
The T790M mutation in the EGFR is relatively common in the patients with acquired resistance to gefitinib. However, mechanisms other than T790M, MET, and HGF status are involved in resistance to gefitinib.
Onitsuka
Takamitsu
T
Second Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan.
Uramoto
Hidetaka
H
Nose
Naohiro
N
Takenoyama
Mitsuhiro
M
Hanagiri
Takeshi
T
Sugio
Kenji
K
Yasumoto
Kosei
K
D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D056726:Genetic Association Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines / Q000627:therapeutic use*
D011799:Quinazolines; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib