What question did this study set out to answer?

This research aims to explore mechanisms of resistance to amivantamab-lazertinib by targeting Ahr in EGFR-mutant lung cancer.

April 5, 2026

Abstract 407: Targeting AhR suppresses the generation of amivantamab-lazertinib-induced drug-tolerant persisters in EGFR-mutant lung cancer.

Key Points

This research aims to explore mechanisms of resistance to amivantamab-lazertinib by targeting Ahr in EGFR-mutant lung cancer.
Established patient-derived xenograft models using tumor samples from an EGFR exon 19 deletion patient.
Treated mice with amivantamab-lazertinib, followed by multi-omics analyses including RNA sequencing and whole-exome sequencing.
Conducted flow cytometry and luciferase assays to measure Ahr expression and drug binding.
Performed in vitro assays to evaluate the effects of DA-4505, an Ahr antagonist, on growth inhibition.
Identified Ahr as one of the most upregulated genes in drug-tolerant persister cells after exposure to amivantamab-lazertinib.
Confirmed lazertinib acts as an Ahr agonist, enhancing Ahr expression in non-small cell lung cancer cell lines.
DA-4505 significantly increased growth inhibition in patient-derived cells, with evidence of additive effects in colony assays.
Early clinical data indicate DA-4505 is well-tolerated as a monotherapy up to 400 mg.

Abstract

Abstract Introduction: In 2024, the U.S. FDA approved first-line amivantamab-lazertinib based on the MARIPOSA trial, which showed superior overall survival compared with osimertinib. However, mechanisms of resistance to this dual-target therapy remain poorly understood. Using multi-omics analyses of patient-derived and preclinical models, we identified the aryl hydrocarbon receptor (AhR) as a potential target to overcome amivantamab-lazertinib resistance. Methods: Fresh tumor samples from a treatment-naïve EGFR exon 19 deletion patient were transplanted into athymic nude mice to establish patient-derived xenograft (PDX) models. Mice were treated with amivantamab-lazertinib for 10 days, followed by single-cell and bulk RNA sequencing, whole-exome sequencing, and immunohistochemistry to assess early-phase responses. In vitro, flow cytometry measured lazertinib-induced AhR expression, and HepG2 AhR-luciferase reporter assays evaluated lazertinib-AhR binding. In silico docking (SAMSON) assessed binding affinity. CellTiter-Glo and colony-formation assays tested combinatorial effects of amivantamab, lazertinib, and DA-4505, an investigational AhR antagonist. Results: Single-cell RNA-seq identified AhR among the most upregulated genes in drug-tolerant persister (DTP) cells after amivantamab-lazertinib exposure. Docking analysis suggested lazertinib acts as an AhR agonist. FACS confirmed that the combination markedly increased AhR expression across NSCLC cell lines. Adding DA-4505 enhanced growth inhibition in H1975 and YU-1185 patient-derived cells, with colony assays confirming additive effects. Transcriptomic and phospho-flow analyses indicated that cell lines with activated Src signaling were most sensitive to triple-drug treatment. Early clinical data from a phase I trial showed DA-4505 monotherapy was well tolerated up to 400 mg. Conclusion: Targeting AhR with DA-4505 augments the efficacy of amivantamab-lazertinib and may mitigate resistance in EGFR-mutant NSCLC. Ongoing clinical evaluation will determine its translational potential. Citation Format: Joo Sung Shim, Mi Hyun Kim, Heekyung Han, Seongsu Jeong, Jae-Hwan Kim, Mi Ran Yun, Sun Min Lim, Byoung Chul Cho. Targeting AhR suppresses the generation of amivantamab-lazertinib-induced drug-tolerant persisters in EGFR-mutant lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 407.

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