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Combined Inhibition of Rad51 and Wee1 Enhances Cell Killing in HNSCC Through Induction of Apoptosis Associated With

Antje Lindemann1, Ameeta A Patel2, Lin Tang3

  • 1Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Molecular Cancer Therapeutics
|May 5, 2021
PubMed

Insights

Combining Rad51 inhibitor (B02) and Wee1 inhibitor (AZD1775) shows promise for treating head and neck squamous cell carcinoma (HNSCC). This novel therapy effectively targets HPV-positive HNSCC by inducing DNA damage and replication stress.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Advanced head and neck squamous cell carcinoma (HNSCC) has limited treatment options and poor survival rates.
  • Exploiting DNA damage and replication stress responses is a novel cancer treatment strategy.
  • Wee1 kinase and Rad51 recombinase are key regulators of replication stress and DNA repair.

Purpose of the Study:

  • To investigate the combined efficacy of a Rad51 inhibitor (B02) and a Wee1 inhibitor (AZD1775) in HNSCC.
  • To explore the underlying mechanisms of synergy and differential sensitivity in HPV-positive versus HPV-negative HNSCC.
  • To assess the potential of this combination as a synthetic lethal therapy.

Main Methods:

  • In vitro and in vivo studies using various HNSCC cell lines and mouse models.
  • Clonogenic survival assays to evaluate drug synergy.
  • Analysis of DNA damage, replication stress markers (e.g., Chk1 phosphorylation, CDK1 activation), and apoptosis.
  • Correlation of Rad51 mRNA expression with patient survival.
  • Assessment of radiosensitization effects.

Main Results:

  • B02 and AZD1775 demonstrated synergy in vitro across all tested HNSCC cell lines.
  • The combination induced excessive DNA damage, replication stress, aberrant mitosis, and apoptosis.
  • Elevated Rad51 mRNA expression correlated with poorer survival in HPV-positive HNSCC patients.
  • The drug combination significantly inhibited tumor growth in vivo in HPV-positive HNSCC models.
  • HPV-positive tumors showed greater sensitivity due to higher endogenous replication stress.
  • B02 enhanced radiosensitivity in HPV-negative HNSCC both in vitro and in vivo.

Conclusions:

  • The combination of Rad51 and Wee1 inhibitors represents a promising synthetic lethal therapeutic strategy for HNSCC.
  • This approach is particularly effective in high-risk HPV-positive HNSCC.
  • The findings suggest a potential new treatment avenue for patients with limited therapeutic options.

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