start-ver=1.4
cd-journal=joma
no-vol=104
cd-vols=
no-issue=11
article-no=
start-page=1440
end-page=1446
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2013
dt-pub=201311
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Non-small-cell lung cancers with epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs); however, unlike cytotoxic agents, it is generally accepted that minimal doses of drugs inhibiting target molecules are sufficient when molecular-targeted agents, including EGFR-TKIs, are used. Thus, any utility of higher doses remains unclear. We compared low-dose (15mg/kg) gefitinib therapy with high-dose (50mg/kg) therapy using an EGFR-mutated lung cancer xenograft model. Both gefitinib doses induced tumor shrinkage, but tumors regrew in the low-dose group within 1month, whereas tumors in the high-dose group did not. Neither the T790M mutation nor MET amplification was apparent in regrown tumors. We also compared outcomes after two doses of gefitinib (5 and 25mg/kg) in a transgenic EGFR-mutated lung cancer mouse model. In line with the results obtained using the xenograft model, both gefitinib doses completely inhibited tumor growth, but tumors treated with the lower dose of gefitinib developed earlier drug resistance. In conclusion, a low gefitinib dose caused tumors to become drug-resistant prior to acquisition of the T790M mutation or MET amplification in EGFR-mutated models of lung cancer. This suggests that it is important to optimize the EGFR-TKI dose for treatment of EGFR mutation-associated lung cancer. Gefitinib may need to be given at a dose greater than the minimum required for inhibition of target molecules.
en-copyright=
kn-copyright=

en-aut-name=HayakawaHiromi
en-aut-sei=Hayakawa
en-aut-mei=Hiromi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NinomiyaTakashi
en-aut-sei=Ninomiya
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YasugiMasayuki
en-aut-sei=Yasugi
en-aut-mei=Masayuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TakataSaburo
en-aut-sei=Takata
en-aut-mei=Saburo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=SakaiKatsuya
en-aut-sei=Sakai
en-aut-mei=Katsuya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=MatsumotoKunio
en-aut-sei=Matsumoto
en-aut-mei=Kunio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=TakigawaNagio
en-aut-sei=Takigawa
en-aut-mei=Nagio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=TanimotoMitsune
en-aut-sei=Tanimoto
en-aut-mei=Mitsune
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=KiuraKatsuyuki
en-aut-sei=Kiura
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

affil-num=1
en-affil=
kn-affil=Okayama Univ, Dept Hematol Oncol & Resp Med, Grad Sch Med Dent & Pharmaceut Sci

affil-num=2
en-affil=
kn-affil=Okayama Univ, Dept Hematol Oncol & Resp Med, Grad Sch Med Dent & Pharmaceut Sci

affil-num=3
en-affil=
kn-affil=Natl Hosp Org, Shikoku Canc Ctr, Dept Thorac Oncol

affil-num=4
en-affil=
kn-affil=Okayama Univ, Dept Hematol Oncol & Resp Med, Grad Sch Med Dent & Pharmaceut Sci

affil-num=5
en-affil=
kn-affil=Okayama Univ, Dept Hematol Oncol & Resp Med, Grad Sch Med Dent & Pharmaceut Sci

affil-num=6
en-affil=
kn-affil=Okayama Univ, Dept Hematol Oncol & Resp Med, Grad Sch Med Dent & Pharmaceut Sci

affil-num=7
en-affil=
kn-affil=Kanazawa Univ, Canc Res Inst, Div Tumor Dynam & Regulat

affil-num=8
en-affil=
kn-affil=Kanazawa Univ, Canc Res Inst, Div Tumor Dynam & Regulat

affil-num=9
en-affil=
kn-affil=Kawasaki Med Univ

affil-num=10
en-affil=
kn-affil=Okayama Univ, Dept Hematol Oncol & Resp Med, Grad Sch Med Dent & Pharmaceut Sci

affil-num=11
en-affil=
kn-affil=Okayama Univ Hosp, Dept Resp Med
END