Mutation-dependent activity of BI4020, JND3229, and TQB3804 in an EGFR mutant Ba/F3 cell panel
Year: 2026
Type: preprint
Abstract: Background EGFR C797S impairs the activity of covalent EGFR inhibitors. Several fourth-generation inhibitors have been developed, but comparisons across different experimental systems do not adequately define their relative activity against individual EGFR genotypes. Methods Osimertinib, BI4020, JND3229, and TQB3804 were evaluated in Ba/F3 cells expressing wild-type EGFR or nine mutant variants. Cell viability was assessed by an MTT assay after 96 h of exposure. EGFR and AKT phosphorylation was examined in L858R/C797S-expressing cells after treatment with the inhibitors. Results Osimertinib IC₅₀ values were 1.39–2.84 nM in cells expressing activating mutations with or without T790M, but 419.42–1422.52 nM in cells expressing activating mutations together with C797S. In 19Del/T790M/C797S and L858R/T790M/C797S cells, BI4020 IC₅₀ values were 0.39 and 0.20 nM, respectively, compared with 61.18 and 13.59 nM for JND3229 and 3.85 and 3.42 nM for TQB3804. In L858R/C797S cells, BI4020 and JND3229 showed similar mean IC₅₀ values of 1.40 and 1.49 nM. TQB3804 showed lower IC₅₀ values in C797S compound mutants containing T790M than in the corresponding models without T790M. BI4020, JND3229, and TQB3804 reduced EGFR and AKT phosphorylation in L858R/C797S cells, whereas osimertinib showed little apparent suppression under the same conditions. Conclusions The three fourth-generation inhibitors exhibited distinct genotype-associated activity profiles. These findings support evaluating the complete EGFR mutation profile when comparing C797S-active inhibitors, while further validation in human lung cancer models is required.
Source: Research Square
Institution: Kawasaki Medical School
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225617945