Open AccessSynthetic lethality of PARP and NAMPT inhibition in triple‐negative breast cancer cells
Author(s) -
Bajrami Ilirjana,
Kigozi Asha,
Van Weverwijk Antoinette,
Brough Rachel,
Frankum Jessica,
Lord Christopher J.,
Ashworth Alan
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201250
Subject(s) - olaparib , nicotinamide phosphoribosyltransferase , parp inhibitor , cancer research , nad+ kinase , triple negative breast cancer , poly adp ribose polymerase , breast cancer , synthetic lethality , nicotinamide mononucleotide , nicotinamide adenine dinucleotide , in vivo , cancer , medicine , pharmacology , chemistry , biology , enzyme , dna repair , biochemistry , polymerase , genetics , gene
PARP inhibitors have been proposed as a potential targeted therapy for patients with triple‐negative (ER‐, PR‐, HER2‐negative) breast cancers. However, it is as yet unclear as to whether single agent or combination therapy using PARP inhibitors would be most beneficial. To better understand the mechanisms that determine the response to PARP inhibitors, we investigated whether enzymes involved in metabolism of the PARP substrate, β‐NAD + , might alter the response to a clinical PARP inhibitor. Using an olaparib sensitization screen in a triple‐negative (TN) breast cancer model, we identified nicotinamide phosphoribosyltransferase (NAMPT) as a non‐redundant modifier of olaparib response. NAMPT is a rate‐limiting enzyme involved in the generation of the PARP substrate β‐NAD + and the suppression of β‐NAD + levels by NAMPT inhibition most likely explains these observations. Importantly, the combination of a NAMPT small molecule inhibitor, FK866, with olaparib inhibited TN breast tumour growth in vivo to a greater extent than either single agent alone suggesting that assessing NAMPT/PARP inhibitor combinations for the treatment of TN breast cancer may be warranted.