Secondary mutations of the EGFR gene that confer resistance to mobocertinib in EGFR exon 20 insertion.

Approximately 10% of mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (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 US FDA. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR-TKIs of earlier generations.We chronically exposed Ba/F3 cells transduced with 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 showed 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.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Citation

Akira Hamada, Kenichi Suda, Masaya Nishino, Keiko Obata, Hana Oiki, Tomoyo Fukami, Shota Fukuda, Toshio Fujino, Shuta Ohara, Takamasa Koga, Masato Chiba, Masaki Shimoji, Masaoki Ito, Toshiki Takemoto, Junichi Soh, Yasuhiro Tsutani, Tetsuya Mitsudomi. Secondary mutations of the EGFR gene that confer resistance to mobocertinib in EGFR exon 20 insertion. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2023 Sep 02

PMID: 37666482

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