Targeting AhR suppresses the generation of amivantamab-lazertinib-induced drug-tolerant persisters in EGFR-mutant lung cancer
Presenter: Joosung Shim, MD Session: Novel Antitumor Agents 1 Time: 4/19/2026 2:00:00 PM → 4/19/2026 5:00:00 PM
Authors
Joo Sung Shim 1 , Mi Hyun Kim 2 , Heekyung Han 2 , Seongsu Jeong 2 , Jae-Hwan Kim 1 , Mi Ran Yun 3 , Sun Min Lim 4 , Byoung Chul Cho 5 1 Yonsei University Hospital Cancer Center, Seoul, Korea, Republic of, 2 Yonsei New Il Han Institute for Integrative Lung Cancer Research, Seoul, Korea, Republic of, 3 Yonsei University College of Medicine, Seoul, Korea, Republic of, 4 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of, 5 Yonsei University College of Medicine, Seoul
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.
Disclosure
J. Shim, None.
Cited in
Control: 1019 · Presentation Id: 8794 · Meeting 21436