Overcoming EGFR bypass signal-induced acquired resistance to ALK tyrosine kinase inhibitors in ALK-translocated lung cancer

Masayoshi Miyawaki, Hiroyuki Yasuda, Tetsuo Tani, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Shigenari Nukaga, Toshiyuki Hirano, Ichiro Kawada, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku, Kenzo Soejima

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well-defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALKTKIs. To this end ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-resistance to other ALK-TKIs. Ceritinib and afatinib combination treatment partially restored the sensitivity to ceritinib. Implications: This study proposes a preclinical rationale to use ALK-TKIs and afatinib combination therapy for ALK-translocated lung cancers that have acquired resistance to ALK-TKIs through EGFR pathway activation.

Original languageEnglish
Pages (from-to)106-114
Number of pages9
JournalMolecular Cancer Research
Volume15
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

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Protein-Tyrosine Kinases
Lung Neoplasms
Gene Rearrangement
Non-Small Cell Lung Carcinoma
anaplastic lymphoma kinase
ceritinib
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Overcoming EGFR bypass signal-induced acquired resistance to ALK tyrosine kinase inhibitors in ALK-translocated lung cancer. / Miyawaki, Masayoshi; Yasuda, Hiroyuki; Tani, Tetsuo; Hamamoto, Junko; Arai, Daisuke; Ishioka, Kota; Ohgino, Keiko; Nukaga, Shigenari; Hirano, Toshiyuki; Kawada, Ichiro; Naoki, Katsuhiko; Hayashi, Yuichiro; Betsuyaku, Tomoko; Soejima, Kenzo.

In: Molecular Cancer Research, Vol. 15, No. 1, 01.01.2017, p. 106-114.

Research output: Contribution to journalArticle

Miyawaki, Masayoshi ; Yasuda, Hiroyuki ; Tani, Tetsuo ; Hamamoto, Junko ; Arai, Daisuke ; Ishioka, Kota ; Ohgino, Keiko ; Nukaga, Shigenari ; Hirano, Toshiyuki ; Kawada, Ichiro ; Naoki, Katsuhiko ; Hayashi, Yuichiro ; Betsuyaku, Tomoko ; Soejima, Kenzo. / Overcoming EGFR bypass signal-induced acquired resistance to ALK tyrosine kinase inhibitors in ALK-translocated lung cancer. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 1. pp. 106-114.
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