Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• BRCA2 is a critical cancer driver, and targeting its deficiencies with PARP inhibitors has shown clinical success.
• Emerging resistance to PARP inhibitors necessitates the identification of novel synthetic lethal (SL) targets for BRCA2-deficient cancers.

Purpose of the Study:

• To identify novel plant-derived compounds that induce synthetic lethality in BRCA2-deficient cells.
• To elucidate the molecular target and mechanism of action for identified compounds.
• To validate deoxycytidine kinase (dCK) as a potential therapeutic target for BRCA2-deficient cancers.

Main Methods:

• Performed a BRCA2-centric synthetic lethal screen using South American plant-derived compounds.
• Utilized chemoproteomic approaches to identify the target of the identified compound, Solanocapsine.
• Confirmed target engagement and synthetic lethality using a specific deoxycytidine kinase (dCK) inhibitor (DI-87).
• Investigated the mechanistic differences between dCK and PARP inhibitor-induced synthetic lethality.
• Evaluated the in-vivo efficacy in a xenograft model.

Main Results:

• Identified Solanocapsine, a steroidal alkaloid, as a selective synthetic lethal inducer in BRCA2-deficient cells.
• Deoxycytidine kinase (dCK) was identified as the target responsible for Solanocapsine's BRCA2-linked synthetic lethality.
• dCK inhibition induces synthetic lethality through a mechanism distinct from PARP inhibitors, primarily impacting mitosis.
• dCK inhibition demonstrated in-vivo efficacy in a xenograft model.

Conclusions:

• Deoxycytidine kinase (dCK) is a novel and promising synthetic lethal target for BRCA2-deficient cancers.
• Targeting dCK offers a potential therapeutic strategy independent of PARP inhibitors, addressing resistance mechanisms.
• Fine-tuning nucleotide supply during mitosis is critical for BRCA2-deficient cell survival, highlighting dCK's role.