TY - JOUR
T1 - IGF2 Autocrine-mediated IGF1R activation is a clinically relevant mechanism of osimertinib resistance in Lung Cancer
AU - Manabe, Tadashi
AU - Yasuda, Hiroyuki
AU - Terai, Hideki
AU - Kagiwa, Harumi D.A.
AU - Hamamoto, Junko
AU - Ebisudani, Toshiki
AU - Kobayashi, Keigo
AU - Masuzawa, Keita
AU - Ikemura, Shinnosuke
AU - Kawa, Ichiro D.A.
AU - Hayashi, Yuichiro
AU - Fukui, Kazuhiko
AU - Horimoto, Katsuhisa
AU - Fukunaga, Koichi
AU - Soeji, Kenzo M.A.
N1 - Funding Information:
This work was supported in part by the Japan Society for the Promotion of Science to T. Manabe (grants #17K16059 and #19J12401), H. Terai (grant #18K08184), S. Ikemura (grant #18K15251), and H. Yasuda (grant #17K09667). This work was also supported in part by Takeda Science Foundation to H. Yasuda and H. Terai and by the Development of Diagnostic Technology for Detection of miRNA in Body Fluids grant from the Japan Agency for Medical Research and Development to K. Horimoto (grant #18ae0101016s0105). We thank Mrs. Chinatsu Yonekawa for her excellent technical assistance.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-19-0956
DO - 10.1158/1541-7786.MCR-19-0956
M3 - Article
C2 - 31941753
AN - SCOPUS:85082873664
VL - 18
SP - 549
EP - 559
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 4
ER -