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DNA Damage and Nuclear Anaplasia Induced by Trastuzumab Deruxtecan in Cancer Cells with Variable HER2 Expression and
So Hyeon Kim1, Yoonjung Park1, Ahrum Min1
1Cancer Research Institute, Seoul National University, Seoul, Korea.
Purpose:
Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in various malignancies, including breast and gastric cancers, and is associated with poor prognosis. Although HER2-targeted therapies, such as trastuzumab, improve outcomes in HER2-positive tumors, resistance often develops, and HER2-low tumors remain largely untargeted. Trastuzumab deruxtecan (T-DXd; DS-8201a) is a HER2-targeted antibody-drug conjugate with potent activity in HER2-positive and HER2-low tumors. This study evaluates its antitumor mechanisms and efficacy in HER2-positive, HER2-low, and homologous recombination deficiency (HRD)-associated models.
Materials And Methods:
Effects of T-DXd were assessed in cancer cell lines with diverse HER2 expression and HRD status. In vivo efficacy was evaluated using a xenograft model derived from HER2-low SNU-601 gastric cancer cells.
Results:
T-DXd reduced HER2 phosphorylation and downstream signaling (AKT, ERK) in HER2-positive cells. It induced DNA damage accumulation, as evidenced by increased γH2AX and p-Chk1 expression, and triggered apoptosis through cleaved poly(ADP-ribose) polymerase and caspase-3 activation, confirmed by annexin V staining. Similar effects were observed in HER2-low cells, with greater sensitivity in HRD cells. In xenografts, T-DXd reduced tumor volume by up to 80% at 4 mg/kg and 10 mg/kg. Histological analyses showed decreased Ki-67 and increased apoptosis. Furthermore, T-DXd induced G2/M cell cycle arrest and nuclear anaplasia, suggesting disruption of chromosomal stability as a potential antitumor mechanism. No significant toxicity, including body weight loss, was observed.
Conclusion:
These findings highlight T-DXd's effectiveness in HER2-low and HRD tumors, supporting its broader clinical application, including strategies targeting DNA damage repair pathways.
Insights
Trastuzumab deruxtecan (T-DXd) shows potent antitumor activity in HER2-positive and HER2-low cancers. This antibody-drug conjugate effectively reduces tumor volume and induces apoptosis, even in tumors with homologous recombination deficiency (HRD).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Human epidermal growth factor receptor 2 (HER2) overexpression is common in breast and gastric cancers, often correlating with poor prognosis.
- Existing HER2-targeted therapies like trastuzumab face resistance and are ineffective in HER2-low tumors.
- Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate demonstrating activity against both HER2-positive and HER2-low cancer cells.
Purpose of the Study:
- To evaluate the antitumor mechanisms of T-DXd in various cancer models.
- To assess the efficacy of T-DXd in HER2-positive, HER2-low, and homologous recombination deficiency (HRD)-associated cancers.
- To investigate T-DXd's impact on HER2 signaling, DNA damage, apoptosis, and cell cycle progression.
Main Methods:
- Assessed T-DXd effects on HER2 phosphorylation and downstream signaling (AKT, ERK) in cancer cell lines.
- Quantified DNA damage (γH2AX, p-Chk1) and apoptosis (cleaved PARP, caspase-3, annexin V) post-T-DXd treatment.
- Evaluated in vivo efficacy using a HER2-low gastric cancer xenograft model, assessing tumor volume, Ki-67, apoptosis, and cell cycle arrest.
Main Results:
- T-DXd inhibited HER2 signaling and induced DNA damage and apoptosis in HER2-positive and HER2-low cancer cells.
- Greater sensitivity to T-DXd was observed in homologous recombination deficiency (HRD) contexts.
- In vivo, T-DXd significantly reduced tumor volume (up to 80%) with no observed toxicity, inducing G2/M cell cycle arrest and nuclear anaplasia.
Conclusions:
- T-DXd demonstrates significant antitumor efficacy across HER2-positive, HER2-low, and HRD-associated tumors.
- The findings support the broader clinical application of T-DXd, including combination strategies targeting DNA damage repair pathways.
- T-DXd represents a promising therapeutic option for a wider range of cancer patients, including those with limited treatment options.
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