Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity

Area of Science:

• Oncology
• Cancer Biology
• Genetics

Background:

• Poly (ADP-ribose) polymerase (PARP) inhibitors are effective in cancers with homologous recombination (HR) deficiency.
• Expanding PARP inhibitor utility requires identifying new targets that induce or mimic HR deficiency.

Purpose of the Study:

• To identify novel genetic targets that modify cancer cell response to PARP inhibitors.
• To investigate the role of TP53 induced glycolysis and apoptosis regulator (TIGAR) in PARP inhibitor sensitivity.

Main Methods:

• CRISPR/Cas9-based genome-scale loss-of-function screen using olaparib sensitivity as a readout.
• Analysis of TIGAR expression and its association with patient survival.
• Assessment of TIGAR knockdown effects on cancer cell sensitivity to olaparib, BRCA1, Fanconi anemia pathway, and senescence.

Main Results:

• TP53 induced glycolysis and apoptosis regulator (TIGAR) was identified as a modifier of PARP inhibitor response.
• TIGAR is amplified in multiple cancer types and associated with poor survival in ovarian cancer.
• TIGAR knockdown increased olaparib sensitivity by downregulating BRCA1 and the Fanconi anemia pathway, and induced senescence.

Conclusions:

• TIGAR plays a significant role in regulating cancer cell response to PARP inhibitors.
• TIGAR represents a potential therapeutic target to enhance the efficacy of PARP inhibitors in cancer treatment.
• Targeting TIGAR could extend the clinical application of PARP inhibitors to a broader range of cancer patients.