Identification of factors conferring resistance to trastuzumab deruxtecan in advanced gastric cancer: a translational study from the single-arm, phase II, DESTINY-Gastric06 trial

Abstract

Background Trastuzumab deruxtecan (T-DXd) has revolutionized the therapeutic landscape for HER2-positive gastric cancer (GC). However, tumor heterogeneity poses a significant challenge in overcoming T-DXd resistance. This study aimed to delineate the mechanisms underlying primary and acquired resistance to T-DXd in GC.

Methods We performed single-cell RNA sequencing on GC tumor tissues from the DESTINY-Gastric06 study, including treatment-naive baseline samples and those with primary or acquired resistance to T-DXd. Dimensionality reduction and unsupervised clustering were applied to identify distinct cell clusters within the tumor tissues. High-dimensional weighted gene co-expression network analysis was employed to identify key gene modules associated with T-DXd resistance. Cell-cell communication was analyzed using CellChat. Key findings were experimentally validated through multiplex immunofluorescence, immunohistochemistry, and functional assays in cellular models.

Results Weighted gene co-expression network analysis identified the red and purple modules as being strongly correlated with primary and acquired T-DXd resistance, respectively. Notably, MUC3A was upregulated in patients with primary resistance and its overexpression was identified as a potential predictor of shorter progression-free survival in response to T-DXd therapy. Moreover, cystatin C, a gene implicated in linker cleavage, was upregulated during the development of acquired resistance. Tumor microenvironment profiling revealed that T-DXd initially promoted immune-cell infiltration and enhanced antigen presentation. However, with the development of resistance, the tumor microenvironment shifted to an immunosuppressive state, characterized by reactivation of transforming growth factor-beta signaling and upregulation of programmed cell death protein-1 (PD-1).

Conclusion These findings provide novel insights into mechanisms underlying T-DXd resistance and highlight potential therapeutic targets for overcoming T-DXd resistance in GC.

Keywords

gastric cancer / trastuzumab deruxtecan / resistance

Acknowledgements

The authors gratefully thank all the patients for participating in this study. Funding support for the study was provided by the Beijing Xisike Clinical Oncology Research Foundation (No. Y-2022HER2AZMS-0377 to Z.P.), Beijing Natural Science Foundation (grant number 7242088 to X.W.), and the National Natural Science Foundation of China (grant number 82473050 to X.W.). The funders played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

Author contributions

Bohan Zhang (Investigation, Software, Validation, Visualization, Writing— original draft, Writing— review & editing), Lei Zhang (Formal Analysis, Software), Cheng Liu (Supervision), Tong Xie (Writing— review & editing), Yifan Zhang (Writing— review & editing), Xiao Wu (Writing—review & editing), Yining Chen (Writing—review & editing), Siyuan Cheng (Writing—review & editing), Yang Feng (Writing—review & editing), Yuxin Wang (Writing—review & editing), Erke Gao (Writing—review & editing), Hongquan Zhang (Writing—review & editing), Lin Shen (Resources, Writing—review & editing), Zhi Peng (Funding acquisition, Project administration, Supervision, Writing—review & editing), Xiaofan Wei (Methodology, Supervision, Writing—review & editing).

Supplementary material

Supplementary material is available at PCMEDI online.

Conflicts of interest

The authors disclose no potential conflicts of interest. L.Z. is an employee of Burning Rock Biotech. The research presented in this manuscript was conducted independently and was not funded, sponsored, or directly supported by Burning Rock Biotech.

Ethics statement

This study was approved by the Ethics Committee of Peking University Cancer Hospital in 2021 (approval number: 2021YW90). Informed content was obtained from all patients enrolled for the collection of clinical information and samples, and all tests and procedures were conducted in accordance with the Declaration of Helsinki.

Availability of data and materials

The single-cell RNA sequencing data generated in this study is deposited at the Genome Sequence Archive for Humans with project number HRA012249. All relevant data supporting the key findings of this study are available within the article or from the corresponding author upon reasonable request.

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