Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition

Oncotarget. 2016 Nov 22;7(47):76534-76550. doi: 10.18632/oncotarget.12266.


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.

Keywords: ATR; BRCA; PARP inhibitor; PARP-trapping; homologous recombination.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression
  • Gene Silencing*
  • Homologous Recombination
  • Humans
  • Mice
  • Nuclear Proteins / genetics*
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Transcriptional Activation
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Nuclear Proteins
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • SLFN11 protein, human
  • talazoparib
  • Ataxia Telangiectasia Mutated Proteins
  • olaparib