RESUMO
Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have a poor understanding of the specific genetic vulnerabilities that would make cancer cells susceptible to such a tailored therapy. Moreover, the identification of such vulnerabilities is of interest for targeting BRCA2;p53-deficient tumors that have acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) through loss of PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, we identify various genes involved in DNA repair to be essential for the survival of PARG;BRCA2;p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 as major synthetic lethal interactors of PARG loss. We provide evidence for compromised replication fork progression, DNA single-strand break repair, and Okazaki fragment processing in PARG;BRCA2;p53-deficient cells, alterations that exacerbate the effects of EXO1/FEN1 inhibition and become lethal in this context. Since this sensitivity is dependent on BRCA2 defects, we propose to target EXO1/FEN1 in PARPi-resistant tumors that have lost PARG activity. Moreover, EXO1/FEN1 targeting may be a useful strategy for enhancing the effect of PARG inhibitors in homologous recombination-deficient tumors.
Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Reparo do DNA , Dano ao DNA , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Endonucleases Flap/genética , Endonucleases Flap/metabolismo , Endonucleases Flap/uso terapêutico , Exodesoxirribonucleases/genética , Enzimas Reparadoras do DNA/genéticaRESUMO
BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.
Assuntos
Neoplasias , Neoplasias Ovarianas , Animais , Camundongos , Feminino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Multiômica , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias/genética , Neoplasias Ovarianas/genéticaRESUMO
Histone eviction and chromatin relaxation are important processes for efficient DNA repair. Poly(ADP) ribose (PAR) polymerase 1 (PARP1) is a key mediator of this process, and disruption of PARP1 activity has a direct impact on chromatin structure. PARP inhibitors (PARPis) have been established as a treatment for BRCA1- or BRCA2-deficient tumors. Unfortunately, PARPi resistance occurs in many patients and the underlying mechanisms are not fully understood. In particular, it remains unclear how chromatin remodelers and histone chaperones compensate for the loss of the PARylation signal. In this Opinion article, we summarize currently known mechanisms of PARPi resistance. We discuss how the study of PARP1-mediated chromatin remodeling may help in further understanding PARPi resistance and finding new therapeutic approaches to overcome it.