IGF2 Autocrine-mediated IGF1R activation is a clinically relevant mechanism of osimertinib resistance in Lung Cancer

Tadashi Manabe, Hiroyuki Yasuda, Hideki Terai, Harumi D.A. Kagiwa, Junko Hamamoto, Toshiki Ebisudani, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Ichiro D.A. Kawa, Yuichiro Hayashi, Kazuhiko Fukui, Katsuhisa Horimoto, Koichi Fukunaga, Kenzo M.A. Soeji

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a thirdgeneration EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, nongenetically defined mechanisms are not well evaluated. For a thorough clarification of osimertinib resistance, both genetic and nongenetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for a thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-Autonomous ligand expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a nongenetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level.

Original languageEnglish
Pages (from-to)549-559
Number of pages11
JournalMolecular Cancer Research
Issue number4
Publication statusPublished - 2020 Apr 1

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research


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