TY - JOUR
T1 - MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib
AU - Ninomiya, Kiichiro
AU - Ohashi, Kadoaki
AU - Makimoto, Go
AU - Tomida, Shuta
AU - Higo, Hisao
AU - Kayatani, Hiroe
AU - Ninomiya, Takashi
AU - Kubo, Toshio
AU - Ichihara, Eiki
AU - Hotta, Katsuyuki
AU - Tabata, Masahiro
AU - Maeda, Yoshinobu
AU - Kiura, Katsuyuki
N1 - Funding Information:
We are grateful to Hiromi Nakashima, Kyoko Maeda for the technical support and to Michinori Aoe, Division of Medical Support of Okayama University Hospital, for analyzing of the Short Tandem Repeat Polymerase Chain Reaction Analysis. We also thank Takehiro Matsubara, Biobank of Okayama University Graduate School of Medicine, for analyzing of NGS data and our laboratory colleagues for the useful discussions. This research received a specific grant from JSPS Grants-in-Aid for Scientific Research (Research Activity Start-up KAKEN 26893155) (K.O.), JSPS Grants-in-Aid for Scientific Research (Grant-in-Aid for Young Scientists (B): KAKEN 16K19454) (K.O.), JSPS Grants-in-Aid for Scientific Research (Scientific Research (B): KAKEN 15H04830) (K.O., T.K. and K.K.).
Funding Information:
Competing Interests: K.O. received a research grant from Boehringer-Ingelheim and Novartis Pharmaceuticals, Japan. K.H. received honoraria from AstraZeneca, Eli Lilly Japan, Daiichi-Sankyo Pharmaceutical, Boehringer-Ingelheim, Nihon Kayaku, Taiho Pharmaceutical, Chugai Pharmaceutical, and Sanofi-Aventis. K.H. also received research funding from Eli Lilly Japan, MSD, and Chugai Pharmaceuticals. K.K. received honoraria from Eli Lilly Japan, Nihon Kayaku, AstraZeneca, Daiichi-Sankyo Pharmaceuticals, Chugai Pharmaceuticals, Taiho Pharmaceuticals, Boehringer-Ingelheim, and Sanofi-Aventis. All other authors declare no conflicts of interest regarding this study.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.
AB - As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.
UR - http://www.scopus.com/inward/record.url?scp=85041682903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041682903&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-20326-z
DO - 10.1038/s41598-018-20326-z
M3 - Article
C2 - 29386539
AN - SCOPUS:85041682903
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 1955
ER -