ArticleCancer research2022
Therapy-Induced Senescence Enhances the Efficacy of HER2-Targeted Antibody-Drug Conjugates in Breast Cancer.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 4 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 4 syntheses or guidelines pooled it, 40 citations in OpenAlex.
- Efficacy evaluation of novel targeted drugs in patients with human epidermal growth factor receptor 2-positive breast cancer: A meta-analysis based on multiple sets of clinical data.The Journal of international medical research · 2026Pooled it
- Cellular Senescence and Immunosenescence in Melanoma: Insights From the Tumor Microenvironment.Cancer medicine · 2025Pooled it
- Efficacy and safety of a combination treatment of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2024Pooled it
- Pooled it
- Review
- The double-edged sword of SASP in breast cancer: from tumor suppression to progression and therapy resistance.Frontiers in oncology · 2026Review
- Therapy-induced senescence in breast cancer and cardiovascular disease: a double-edged biological process.Frontiers in cardiovascular medicine · 2026Review
- Cleaning, Chasing and Calming: Promising Paradigms of Senotherapy in Aging-Related Diseases.International journal of biological sciences · 2026Review
- IL33-induced lipid droplet formation in mature low-density neutrophils drives colorectal cancer liver metastasis.Cellular & molecular immunology · 2025Article
- Advancements in antibody-drug conjugates as cancer therapeutics.Journal of the National Cancer Center · 2025Review
- Targeting Resistance Pathways in Breast Cancer Through Precision Oncology: Nanotechnology and Immune Modulation Approaches.Biomedicines · 2025Review
- Article
- Role of Senescence-Associated Biomarkers and Immune Dynamics in Predicting Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.International journal of general medicine · 2025Article
- Machine learning-derived cellular senescence index for predicting prognosis and drug sensitivity in patients with renal cell carcinoma.Frontiers in immunology · 2025Article
- Mechanisms of resistance to antibody-drug conjugates in cancer therapy: molecular basis and therapeutic strategies.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Another power of antibody-drug conjugates: immunomodulatory effect and clinical applications.Frontiers in immunology · 2025Review
- Clinical characteristics and therapeutic direction of HER2 low-expression breast cancer.Frontiers in oncology · 2025Review
- Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors.Nature communications · 2024Article
- Review
- Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect.Journal for immunotherapy of cancer · 2024Article
Corrections and comments
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Authors and funding
18 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Antibody-drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression. SIGNIFICANCE: Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.