A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer

Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. However, tumor relapse suggests additional resistance mutations might emerge. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by cryst...

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Bibliographic Details
Published in:NPJ precision oncology 2024-02, Vol.8 (1), p.46-46, Article 46
Main Authors: Suzuki, Mai, Uchibori, Ken, Oh-hara, Tomoko, Nomura, Yumi, Suzuki, Ryusei, Takemoto, Ai, Araki, Mitsugu, Matsumoto, Shigeyuki, Sagae, Yukari, Kukimoto-Niino, Mutsuko, Kawase, Yusuke, Shirouzu, Mikako, Okuno, Yasushi, Nishio, Makoto, Fujita, Naoya, Katayama, Ryohei
Format: Article
Language:English
Subjects:
631/67/1612/1350
692/4028/67/1059/2326
692/699/67/1612/1350
Antibodies
Cancer Research
Cancer therapies
Chemotherapy
Cloning
Crystal structure
Drug resistance
Drugs
Gene Therapy
Human Genetics
Inhibitor drugs
Internal Medicine
Kinases
Lung cancer
Medical research
Medicine
Medicine & Public Health
Mutagenesis
Mutation
Oncology
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Summary:Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. However, tumor relapse suggests additional resistance mutations might emerge. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by crystal structure analysis and predicted brigatinib-resistant mutations through a cell-based assay including N-ethyl-N-nitrosourea (ENU) mutagenesis. We found that clinically reported L718 and G796 compound mutations appeared, consistent with their proximity to the binding site of brigatinib, and brigatinib-resistant quadruple mutants such as EGFR-activating mutation/T790M/C797S/L718M were resistant to all the clinically available EGFR-TKIs. BI-4020, a fourth-generation EGFR inhibitor with a macrocyclic structure, overcomes the quadruple and major EGFR-activating mutants but not the minor mutants, such as L747P or S768I. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-024-00542-9