title: Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets.
abstract: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively. Subsequent functional validation suggested that inhibition of DCK by niraparib could have detrimental effects when combined with nucleoside analog pro-drugs. H6PD silencing can cause apoptosis and further sensitize cells to PARPi, suggesting that H6PD may be, in addition to its established role in metabolic disorders, a new anticancer target.
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Knezevic
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Wright
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Lily L Remsing
authors.initials: LLR
authors.lastname: Rix
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.|Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Woosuk
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.|Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA.
authors.forename: Brent M
authors.initials: BM
authors.lastname: Kuenzi
authors.affiliation: Chemical Biology Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.|Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA.
authors.forename: January M
authors.initials: JM
authors.lastname: Watters
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Koomen
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Alvaro N
authors.initials: AN
authors.lastname: Monteiro
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.|Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Caius
authors.initials: C
authors.lastname: Radu
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.|Chemical Biology Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
keywords: H6PD; PARP inhibitor; chemical proteomics; polypharmacology; target identification; target selectivity