A Macrocyclic Kinase Inhibitor Overcomes Triple Resistant Mutations in EGFR-positive Lung Cancer

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2024 Feb 24

PMID 38396251

Authors

Mai Suzuki

Ken Uchibori

Tomoko Oh-Hara

Yumi Nomura

Ryusei Suzuki

Ai Takemoto

Mitsugu Araki

Shigeyuki Matsumoto

Yukari Sagae

Mutsuko Kukimoto-Niino

Yusuke Kawase

Mikako Shirouzu

Yasushi Okuno

Makoto Nishio

Naoya Fujita

Ryohei Katayama

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

[Non-small Cell Lung Cancer Cell Line PC-9 Drug-resistant Mutant Cell Line  Establishment and Validation of Their Sensitivity to EGFR Inhibitors].

Hu T, Lou Y, Su M Zhongguo Fei Ai Za Zhi. 2025; 27(11):815-825.

PMID: 39800476 PMC: 11732384. DOI: 10.3779/j.issn.1009-3419.2024.101.31.

Next-generation EGFR tyrosine kinase inhibitors to overcome C797S mutation in non-small cell lung cancer (2019-2024).

Das D, Xie L, Hong J RSC Med Chem. 2024; .

PMID: 39246743 PMC: 11376191. DOI: 10.1039/d4md00384e.

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