Synthetic lethality between CCNE1 hyperactivity and PARG inhibition in breast cancer

Abstract

Abstract Poly(ADP-Ribose) polymerase (PARP) inhibitors have shown wide utility in targeting cancers with defects in homologous recombination. Poly(ADP-ribose) glycohydrolase (PARG), reverses the action of PARP enzymes and may also be an anti-cancer target. Genetic mapping of cellular factors dictating response to a PARG inhibitor by siRNA and CRISPR screens revealed chemical synthetic lethality with loss of base excision repair (BER) machinery also reflected in synergies with therapeutics that induce BER-dependent DNA damage. In a pharmacogenomic screen, Cyclin E1 (CCNE1) expression predicted PARG inhibitor efficacy across a panel of breast cancer cell lines and genetic induction of CCNE1 leads to drug sensitivity. PARG inhibitors cause excessive PAR formation, resulting in loss of cellular NAD + leading to necrosis. Hence, PARG inhibitors selectively kill cells with elevated PAR turnover, by impinging on the BER pathway or CCNE1-induced replication stress, and stalling PAR recycling may lead to runaway PAR accumulation and energy dependent cell death.