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Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer

Author

Listed:
  • Ken Uchibori

    (Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
    Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University)

  • Naohiko Inase

    (Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University)

  • Mitsugu Araki

    (RIKEN Advanced Institute for Computational Science)

  • Mayumi Kamada

    (Graduate School of Medicine, Kyoto University)

  • Shigeo Sato

    (Cancer Chemotherapy Center, Japanese Foundation for Cancer Research)

  • Yasushi Okuno

    (RIKEN Advanced Institute for Computational Science
    Graduate School of Medicine, Kyoto University)

  • Naoya Fujita

    (Cancer Chemotherapy Center, Japanese Foundation for Cancer Research)

  • Ryohei Katayama

    (Cancer Chemotherapy Center, Japanese Foundation for Cancer Research)

Abstract

Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR–TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure–activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.

Suggested Citation

  • Ken Uchibori & Naohiko Inase & Mitsugu Araki & Mayumi Kamada & Shigeo Sato & Yasushi Okuno & Naoya Fujita & Ryohei Katayama, 2017. "Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer," Nature Communications, Nature, vol. 8(1), pages 1-16, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14768
    DOI: 10.1038/ncomms14768
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    Cited by:

    1. K M A Zinnah & Sang-Youel Park, 2019. "Antidepressant Drug Sertraline up-regulates Death Receptor 5 to attenuate TRAIL Resistance in Lung Cancer via Inhibition of Autophagy Flux," Cancer Therapy & Oncology International Journal, Juniper Publishers Inc., vol. 15(1), pages 38-49, October.

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