Synthetic lethality between CCNE1 hyperactivity and PARG inhibition in breast cancer

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.

Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation

“…Importantly, NS reverts all the molecular and cell cycle phenotypes associated with PARGi sensitivity, with the exception of PAR chain accumulation. (x) And finally, we show that inhibition of thymidylate synthase, a key enzyme required for dNTP homeostasis ( 88 ), sensitizes several ovarian cancer cells lines to PARGi, as also observed by others ( 90 ). In this Discussion, we synthesise these observations to address three questions.…”

“…Several other genes emerged as possible PARGi sensitizers, including CTPS2 , TK1 , DUT (pyrimidine biosynthesis genes) as well as POLB , FEN1 , LIG1 (BER genes), although their effects were more modest and/or limited to one or two cell lines, highlighting that there may be cell-line-specific redundancies and different buffering capacities. However, TYMS , DUT , POLB , LIG1 and FEN1 have been identified by others as PARGi synthetic lethality genes ( 90 , 91 ), and these observations support the notion that inhibition of nucleotide biosynthesis and BER can sensitize cancer cells to pharmacological PARG inhibition.…”