Addition of S-1 to the epidermal growth factor receptor inhibitor gefitinib overcomes gefitinib resistance in non-small cell lung cancer cell lines with MET amplification.
OBJECTIVE
Most non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET proto-oncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines.


METHODS
The effects of gefitinib on EGFR signaling and on the expression both of thymidylate synthase and of the transcription factor E2F-1 in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of S-1 (or 5-fluorouracil) and gefitinib on the growth of NSCLC cells were examined in vitro as well as in nude mice.


RESULTS
Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR. The combination of 5-fluorouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, but not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification.


CONCLUSIONS
Our results suggest that the addition of S-1 to EGFR-TKIs is a promising strategy to overcome EGFR-TKI resistance in NSCLC with MET amplification.
Okabe
Takafumi
T
Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
Okamoto
Isamu
I
Tsukioka
Sayaka
S
Uchida
Junji
J
Hatashita
Erina
E
Yamada
Yuki
Y
Yoshida
Takeshi
T
Nishio
Kazuto
K
Fukuoka
Masahiro
M
Jänne
Pasi A
PA
Nakagawa
Kazuhiko
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D050687:E2F1 Transcription Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005472:Fluorouracil / Q000008:administration & dosage; D000077156:Gefitinib; D005784:Gene Amplification; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010094:Oxonic Acid / Q000008:administration & dosage*; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage*; D005641:Tegafur / Q000008:administration & dosage*; D013940:Thymidylate Synthase / Q000378:metabolism
D004338:Drug Combinations; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D013940:Thymidylate Synthase; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib; D005472:Fluorouracil