title: Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition.
abstract: Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5 °C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized on-demand induction of HR deficiency, an approach that we term induced synthetic lethality.
authors.affiliation: Van Leeuwenhoek Centre for Advanced Microscopy-AMC, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Przemek M
authors.initials: PM
authors.lastname: Krawczyk
authors.forename: Berina
authors.initials: B
authors.lastname: Eppink
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
authors.forename: Jan
authors.initials: J
authors.lastname: Stap
authors.forename: Hans
authors.initials: H
authors.lastname: Rodermond
authors.forename: Hanny
authors.initials: H
authors.lastname: Odijk
authors.forename: Alex
authors.initials: A
authors.lastname: Zelensky
authors.forename: Chris
authors.initials: C
authors.lastname: van Bree
authors.forename: Lukas J
authors.initials: LJ
authors.lastname: Stalpers
authors.forename: Marrije R
authors.initials: MR
authors.lastname: Buist
authors.forename: Thomas
authors.initials: T
authors.lastname: Soullié
authors.forename: Joost
authors.initials: J
authors.lastname: Rens
authors.forename: Hence J M
authors.initials: HJ
authors.lastname: Verhagen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Nicolaas A P
authors.initials: NA
authors.lastname: Franken
authors.forename: Timo L M
authors.initials: TL
authors.lastname: Ten Hagen
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Aten
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D015151:Immunoblotting; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D024682:BRCA2 Protein; D016227:Benzoquinones; D004268:DNA-Binding Proteins; D047029:Lactams, Macrocyclic; C115774:NU 1025; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; C110901:X-ray repair cross complementing protein 3; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib