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