Abstract 3166: TKI adaptive resistance in HER2-driven non-small cell lung cancer at minimal residual disease stage can be targeted using cell surface-directed therapies

Abstract Background: HER2 mutations drive 1-2% of non-small cell lung cancers (NSCLCs), and recent HER2-directed antibody-drug conjugates and tyrosine kinase inhibitors (TKIs) such as trastuzumab-deruxtecan and zongertinib have significantly improved outcomes. However, these approaches remain non-curative, and nearly all patients develop progressive disease. Novel strategies capable of eliminating minimal residual disease (MRD) are urgently needed. Generating cell-surface-directed therapies that recognize cell membrane proteins present or upregulated upon TKI adaptation remain underdeveloped in the HER2 space due to lack of cell surface dynamic characterization. Methods: HER2-mutant NSCLC cell lines were treated with zongertinib at varying doses to establish sensitivity values (CellTiter-Glo). A HER2-mutant, zongertinib-insensitive small cell lung cancer line (H446) served as a negative control. Total and cell surface expression of targetable receptors and markers amplified in lung cancers were quantified by western blot and flow cytometry in both, TKI-naïve and TKI-tolerant states (IC50 and IC90 zongertinib exposure). HER2-driven (TKI sensitive and resistant) and control lines were then treated with cell-surface-directed therapies for 24 hours and evaluated for their toxicity. Results: We demonstrate that HER2-mutant NSCLC cell lines retained demonstrated dynamic changes in cell surface protein expression in treatment-naïve versus zongertinib-induced MRD states. TKI-sensitive and TKI-resistant HER2-driven lines demonstrated high sensitivity to therapies targeting surface proteins, which correlated with their level of expression. Conclusions: HER2-driven NSCLC cell lines present dynamic changes in cell surface proteins when undergoing TKI treatment. These proteins can be successfully targeted to eradicate residual NSCLC after TKI treatment, supporting this avenue as a rational therapeutic strategy for eradicating MRD and preventing relapse in HER2-mutant NSCLC. Ongoing studies will inform advancement toward early-phase clinical trials with curative intent. Citation Format: Manale El Kharbili, Daniel Wilkinson, Lauren Giesy, Sharon R. Pine, Peter Fecci, Kyle Concannon. TKI adaptive resistance in HER2-driven non-small cell lung cancer at minimal residual disease stage can be targeted using cell surface-directed therapies [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 3166.