Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells.
Huan LiSrinivas ChatlaXiaolei LiuUmeshkumar VekariyaDongwook KimMatthew WaltZhaorui LianGeorge MortonZijie FengDan YangHongjun LiuKatherine ReedWayne ChildersXiang YuJozef MadzoKumaraswamy Naidu ChitralaTomasz SkorskiJian HuangPublished in: Research square (2023)
Poly (ADP-ribose) polymerase (PARP) inhibitors represent a promising new class of agents that have demonstrated efficacy in treating various cancers, particularly those that carry BRCA1/2 mutations. The cancer associated BRCA1/2 mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPis) have been applied to trigger synthetic lethality in BRCA1/2 -mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, resistance to PARPis is common and can occur through multiple mechanisms, including the restoration of HR and/or the stabilization of replication forks. To gain a better understanding of the mechanisms underlying PARPi resistance, we conducted an unbiased CRISPR-pooled genome-wide library screen to identify new genes whose deficiency confers resistance to the PARPi olaparib. Our study revealed that ZNF251, a transcription factor, is a novel gene whose haploinsufficiency confers PARPi resistance in multiple breast and ovarian cancer lines harboring BRCA1 mutations. Mechanistically, we discovered that ZNF251 haploinsufficiency leads to constitutive stimulation of DNA-PKcs-dependent non-homologous end joining (NHEJ) repair of DSBs and DNA-PKcs-mediated fork protection in BRCA1 -mutated cancer cells (BRCA1mut + ZNF251 KD). Moreover, we demonstrated that DNA-PKcs inhibitors can restore PARPi sensitivity in BRCA1mut + ZNF251 KD cells ex vivo and in vivo . Our findings provide important insights into the mechanisms underlying PARPi resistance and highlight the unexpected role of DNA-PKcs in this phenomenon.
Keyphrases
- circulating tumor
- dna repair
- genome wide
- cell free
- dna damage
- single molecule
- breast cancer risk
- transcription factor
- nucleic acid
- induced apoptosis
- cell cycle arrest
- copy number
- cell death
- gene expression
- dna methylation
- cell proliferation
- randomized controlled trial
- signaling pathway
- dna binding
- young adults
- pi k akt
- endoplasmic reticulum stress