DNA Damage Response Inhibitor Combinations Exert Synergistic Antitumor Activity in Aggressive B-Cell Lymphomas

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genomics

Background:

• The DNA damage response (DDR) pathway, involving kinases ATR, Chk1, and Wee1, is crucial for managing replication stress and maintaining genomic stability in cancer.
• Inhibitors targeting these DDR kinases are in clinical development.
• Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive B-cell lymphomas with poor prognoses, exhibiting dependency on Chk1 and Wee1 for survival.

Purpose of the Study:

• To investigate the preclinical efficacy of the ATR inhibitor AZD6738, alone and in combination with Chk1 (AZD7762) or Wee1 (AZD1775) inhibitors.
• To evaluate these combinations in MCL and DLBCL models, assessing both in vitro and in vivo activity.
• To elucidate the cellular and molecular mechanisms underlying the observed synergistic effects.

Main Methods:

• Screening of multiple MCL and DLBCL cell lines in vitro for sensitivity to single-agent and combination treatments.
• Validation of promising combinations using in vivo preclinical models.
• Analysis of cellular and molecular mechanisms, including cell cycle progression, DNA damage, and protein level changes.
• Pharmacodynamic assessment of in vivo samples.

Main Results:

• AZD6738 demonstrated significant synergistic cytotoxicity when combined with AZD7762 or AZD1775 in both MCL and DLBCL cell lines, irrespective of TP53, MYC, or ATM mutation status.
• The combination treatments induced marked S-phase delay, increased cyclin-dependent kinase (CDK) activity, elevated DNA damage, and reduced levels of Wee1, MYC, and RRM2 proteins.
• Synergistic in vitro activity translated to potent in vivo antitumor effects.

Conclusions:

• Combinations of DDR inhibitors, specifically ATR inhibitors with Chk1 or Wee1 inhibitors, exhibit strong synergistic activity in preclinical models of MCL and DLBCL.
• These findings suggest that DDR-DDR inhibitor combinations represent a promising novel therapeutic strategy for patients with these aggressive B-cell lymphomas.