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

PDF | HTML | Supplementary Files | Order a Reprint

DOI: 10.18632/oncotarget.12266

Junko Murai1, Ying Feng2, Guoying K. Yu2, Yuanbin Ru2, Sai-Wen Tang1,3, Yuqiao Shen2 and Yves Pommier1

1 Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

2 BioMarin Pharmaceutical Inc., Novato, CA, USA

3 Current affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stranford University School of Medicine, Stanford, CA, USA

Correspondence to:

Yves Pommier, email: pommier@nih.gov

Keywords: PARP-trapping, ATR, PARP inhibitor, BRCA, homologous recombination

Received: August 25, 2016 Accepted: August 26, 2016 Published: September 27, 2016

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.