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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Osimertinib resistance in EGFR-mutant lung cancer often involves C797S mutations.
• Brigatinib is effective against some osimertinib-resistant EGFR mutations but acquired resistance can still develop.
• Emerging resistance mechanisms necessitate the development of next-generation inhibitors.

Purpose of the Study:

• To elucidate the binding mode of brigatinib to EGFR-T790M/C797S mutants.
• To identify novel brigatinib-resistant mutations.
• To evaluate the efficacy of a fourth-generation EGFR inhibitor, BI-4020, against emerging resistance mutations.

Main Methods:

• Crystal structure analysis of brigatinib bound to EGFR-T790M/C797S.
• Cell-based mutagenesis assays using N-ethyl-N-nitrosourea (ENU) to predict resistance mutations.
• Molecular dynamics simulations to assess binding affinity of BI-4020 to EGFR mutants.

Main Results:

• Clinically relevant L718 and G796 mutations were identified as brigatinib resistance mutations.
• Brigatinib-resistant quadruple mutants (e.g., EGFR-activating mutation/T790M/C797S/L718M) showed resistance to all available EGFR-TKIs.
• BI-4020 demonstrated efficacy against quadruple and major EGFR mutants but not minor mutants like L747P or S768I.

Conclusions:

• Brigatinib resistance can arise from specific mutations near the binding site.
• Emerging quadruple EGFR mutants represent a significant clinical challenge.
• Fourth-generation macrocyclic inhibitors like BI-4020 show promise in overcoming certain resistance mechanisms, guiding future therapeutic strategies.