ArticleJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2026
Loss of Payload Sensitivity and Other Mechanisms of Resistance to T-DXd in HER2-Mutant NSCLC: Implications for Subsequent Responsiveness to HER2 TKIs.
Article in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Who cites it
7 citing papers in PubMed.
- Antibody-Drug Conjugates in Lung Cancer: Promise, Progress, and Persistent Challenges.Current issues in molecular biology · 2026Review
- New Treatment Strategies for Rare Genomic Alterations:Cancers · 2026Review
- Review
- HER2 Alterations in Squamous Cell Lung Cancer: Biology, Therapeutic Landscape, and Emerging Precision Approaches.Cancers · 2026Review
- Chemotherapy in combination with KRAS inhibitors inJournal of thoracic disease · 2026Article
- Review
- HER2-ADC and HER2-TKI Overcomes HER2 Amplification as an Acquired Resistance to Zongertinib - A Case Report.Lung Cancer (Auckland, N.Z.) · 2026Article
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Authors and funding
32 authors.
Funding
Abstract
introductionEffective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed.
methodsUsing preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches.
resultsWe determined that acquired resistance to T-DXd could occur through multiple mechanisms including payload resistance which could be mediated by SFLN11 loss and copy number gains in the efflux pump ABCC1/MRP1. Moreover, T-DXd resistance could be mediated by secondary HER2 extracellular mutations in domain IV, the trastuzumab binding site. Tumor cells with acquired payload resistance or domain IV mutations maintained HER2 signaling and remained sensitive to HER2 TKIs, including zongertinib or poziotinib. Likewise, patients with HER2-mutant NSCLC treated with poziotinib demonstrated similar response rates regardless of prior T-DXd.
conclusionsIn patients with HER2-mutant NSCLC, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness.
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