Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• WEE1 and CHEK1 (CHK1) kinases regulate cell cycle checkpoints and DNA damage response.
• WEE1 inhibitor AZD1775 and CHK1 inhibitor SRA737 are in clinical trials but underexplored in prostate cancer.
• Elevated WEE1 and CHK1 expression is observed in castration-resistant (CRPC) and neuroendocrine prostate cancer (NEPC).

Purpose of the Study:

• To evaluate the efficacy of WEE1 inhibitor AZD1775 and CHK1 inhibitor SRA737 in prostate cancer models.
• To investigate the combination therapy of AZD1775 and SRA737 in CRPC and NEPC.
• To elucidate the underlying mechanisms of action for these inhibitors in prostate cancer.

Main Methods:

• In vitro studies using CRPC and NEPC cell lines and tumor spheroids.
• In vivo studies using a transgenic mouse model of NEPC.
• Assessment of cell viability, IC50 values, tumor growth, survival, and metastasis.
• Mechanistic studies on feedback activation of CHK1 and DNA damage accumulation.

Main Results:

• Both AZD1775 and SRA737 demonstrated potent cell killing, with SRA737 showing time-dependent effects.
• The combination of AZD1775 and SRA737 synergistically reduced viability in CRPC cell lines and spheroids.
• In vivo, SRA737 alone and in combination with AZD1775 suppressed tumor growth, improved survival, and reduced metastasis in NEPC models.
• SRA737 blocked AZD1775-induced CHK1 feedback activation, leading to increased mitotic entry and DNA damage.

Conclusions:

• CHK1 inhibitor SRA737 exhibits significant single-agent anticancer activity in NEPC models.
• The combination of SRA737 and AZD1775 demonstrates synergistic efficacy against CRPC and NEPC.
• SRA737 alone or in combination with AZD1775 represents a promising therapeutic strategy for advanced prostate cancers.