TY - JOUR
T1 - Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A
AU - Chiba, Masato
AU - Togashi, Yosuke
AU - Bannno, Eri
AU - Kobayashi, Yoshihisa
AU - Nakamura, Yu
AU - Hayashi, Hidetoshi
AU - Terashima, Masato
AU - De Velasco, Marco A.
AU - Sakai, Kazuko
AU - Fujita, Yoshihiko
AU - Mitsudomi, Tetsuya
AU - Nishio, Kazuto
N1 - Funding Information:
Y. Togashi has received a lecture fee from Boehringer-Ingelheim, T. Mitsudomi has received lecture fees from Astra-Zeneca, Boehringer-Ingelheim, Chugai and Pfizer and research funding from Astra-Zeneca, Boehringer-Ingelheim, Chugai and Pfizer. K. Nishio has received lecture fees from Chugai, Daiichi Sankyo and Sumitomo Bakelite. The other authors do not have any potential conflicts of interest to report.
Funding Information:
This study was supported in part by a Grant-in-Aid for Research Activity start-up (Y. Togashi; 15H06754). None of the funding bodies played a role in data collection, analysis, or interpretation of data, the writing of the manuscript, or the decision to submit the manuscript for publication.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/4/19
Y1 - 2017/4/19
N2 - Background: Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second- or third-generation EGFR-TKIs. Methods: Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated. Results: Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second- and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone. Conclusions: Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.
AB - Background: Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second- or third-generation EGFR-TKIs. Methods: Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated. Results: Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second- and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone. Conclusions: Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.
KW - D761Y
KW - EGFR mutation
KW - Irreversible EGFR-TKI
KW - L747S
KW - Secondary resistant mutation
KW - T854A
UR - http://www.scopus.com/inward/record.url?scp=85019051749&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019051749&partnerID=8YFLogxK
U2 - 10.1186/s12885-017-3263-z
DO - 10.1186/s12885-017-3263-z
M3 - Article
C2 - 28424065
AN - SCOPUS:85019051749
SN - 1471-2407
VL - 17
JO - BMC cancer
JF - BMC cancer
IS - 1
M1 - 281
ER -
