title: Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition.
abstract: Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs.
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Murai
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Guoying K
authors.initials: GK
authors.lastname: Yu
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Yuanbin
authors.initials: Y
authors.lastname: Ru
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Current affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stranford University School of Medicine, Stanford, CA, USA.
authors.forename: Sai-Wen
authors.initials: SW
authors.lastname: Tang
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C576668:SLFN11 protein, human; C586365:talazoparib; D064007:Ataxia Telangiectasia Mutated Proteins; C531550:olaparib
keywords: ATR; BRCA; PARP inhibitor; PARP-trapping; homologous recombination