title: ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells.
abstract: Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Yazinski
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Valentine
authors.initials: V
authors.lastname: Comaills
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Rémi
authors.initials: R
authors.lastname: Buisson
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Marie-Michelle
authors.initials: MM
authors.lastname: Genois
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Hai Dang
authors.initials: HD
authors.lastname: Nguyen
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Chu Kwen
authors.initials: CK
authors.lastname: Ho
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Howard Hughes Medical Institute, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Todorova Kwan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Morris
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Massachusetts General Hospital Gillette Center, Massachusetts General Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Lauffer
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Howard Hughes Medical Institute, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Massachusetts General Hospital Gillette Center, Massachusetts General Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics; D004260:DNA Repair; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004273:DNA, Neoplasm; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATR; BRCA-deficient cancer; PARP inhibitor