TY - JOUR
T1 - Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition
AU - Krawczyk, Przemek M.
AU - Eppink, Berina
AU - Essers, Jeroen
AU - Stap, Jan
AU - Rodermond, Hans
AU - Odijk, Hanny
AU - Zelensky, Alex
AU - van Bree, Chris
AU - Stalpers, Lukas J.
AU - Buist, Marrije R.
AU - Soullié, Thomas
AU - Rens, Joost
AU - Verhagen, Hence J. M.
AU - O'Connor, Mark J.
AU - Franken, Nicolaas A. P.
AU - ten Hagen, Timo L. M.
AU - Kanaar, Roland
AU - Aten, Jacob A.
PY - 2011
Y1 - 2011
N2 - 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
AB - 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
U2 - https://doi.org/10.1073/pnas.1101053108
DO - https://doi.org/10.1073/pnas.1101053108
M3 - Article
C2 - 21555554
SN - 0027-8424
VL - 108
SP - 9851
EP - 9856
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
IS - 24
ER -