T790米
医学
奥西默替尼
癌症研究
埃罗替尼
外显子
吉非替尼
突变
表皮生长因子受体抑制剂
表皮生长因子受体
抗性突变
后天抵抗
抗药性
基因突变
癌症
基因
遗传学
生物
内科学
聚合酶链反应
逆转录酶
作者
Akira Hamada,Kenichi Suda,Masaya Nishino,Keiko Obata,Hana Oiki,Teiichi Fukami,Shota Fukuda,Toshio Fujino,Shuta Ohara,Toshihiko Kinoshita,Masato Chiba,Masaki Shimoji,Masaoki Ito,Toshiki Takemoto,Junichi Soh,Yasuhiro Tsutani,Tetsuya Mitsudomi
标识
DOI:10.1016/j.jtho.2023.08.029
摘要
Approximately 10% of mutations in the EGFR gene in NSCLC are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR tyrosine kinase inhibitors (TKIs). Several novel EGFR TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the U.S. Food and Drug Administration. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR TKIs of earlier generations.We chronically exposed murine pro-B-cell line cells transduced with the five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations.All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH, and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib exhibited good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR TKIs, except for erlotinib, which was active for insFQEA with C797S.T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.
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