Activation of EGFR bypass signaling by TGFa overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells

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

Research output: Contribution to journalArticle

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Abstract

Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122- AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho- RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFα, one of the EGFR ligands, was significantly increased and knockdown of TGFα restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling.

Original languageEnglish
Pages (from-to)162-171
Number of pages10
JournalMolecular Cancer Therapeutics
Volume15
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1

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Lung Neoplasms
Non-Small Cell Lung Carcinoma
Gene Rearrangement
CH5424802
Receptor Protein-Tyrosine Kinases
Heterografts
Western Blotting
Phosphorylation
Ligands
Cell Line
Mutation
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Activation of EGFR bypass signaling by TGFa overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells. / Tani, Tetsuo; Yasuda, Hiroyuki; Hamamoto, Junko; Kuroda, Aoi; Arai, Daisuke; Ishioka, Kota; Ohgino, Keiko; Miyawaki, Masayoshi; Kawada, Ichiro; Naoki, Katsuhiko; Hayashi, Yuichiro; Betsuyaku, Tomoko; Soejima, Kenzo.

In: Molecular Cancer Therapeutics, Vol. 15, No. 1, 01.01.2016, p. 162-171.

Research output: Contribution to journalArticle

Tani, Tetsuo ; Yasuda, Hiroyuki ; Hamamoto, Junko ; Kuroda, Aoi ; Arai, Daisuke ; Ishioka, Kota ; Ohgino, Keiko ; Miyawaki, Masayoshi ; Kawada, Ichiro ; Naoki, Katsuhiko ; Hayashi, Yuichiro ; Betsuyaku, Tomoko ; Soejima, Kenzo. / Activation of EGFR bypass signaling by TGFa overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 1. pp. 162-171.
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