Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model

Hiromi Hayakawa, Eiki Ichihara, Kadoaki Oohashi, Takashi Ninomiya, Masayuki Yasugi, Saburo Takata, Katsuya Sakai, Kunio Matsumoto, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

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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 (15 mg/kg) gefitinib therapy with high-dose (50 mg/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 1 month, 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 25 mg/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.

Original languageEnglish
Pages (from-to)1440-1446
Number of pages7
JournalCancer Science
Volume104
Issue number11
DOIs
Publication statusPublished - Nov 2013

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Epidermal Growth Factor Receptor
Lung Neoplasms
Mutation
Neoplasms
Protein-Tyrosine Kinases
Heterografts
gefitinib
Cytotoxins
Drug Resistance
Non-Small Cell Lung Carcinoma
Pharmaceutical Preparations
Therapeutics
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model. / Hayakawa, Hiromi; Ichihara, Eiki; Oohashi, Kadoaki; Ninomiya, Takashi; Yasugi, Masayuki; Takata, Saburo; Sakai, Katsuya; Matsumoto, Kunio; Takigawa, Nagio; Tanimoto, Mitsune; Kiura, Katsuyuki.

In: Cancer Science, Vol. 104, No. 11, 11.2013, p. 1440-1446.

Research output: Contribution to journalArticle

Hayakawa, Hiromi ; Ichihara, Eiki ; Oohashi, Kadoaki ; Ninomiya, Takashi ; Yasugi, Masayuki ; Takata, Saburo ; Sakai, Katsuya ; Matsumoto, Kunio ; Takigawa, Nagio ; Tanimoto, Mitsune ; Kiura, Katsuyuki. / Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model. In: Cancer Science. 2013 ; Vol. 104, No. 11. pp. 1440-1446.
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