Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 24, Pages 9851-9856Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1101053108
Keywords
anti-cancer treatment; RAD51; double-strand break
Categories
Funding
- European Community [FP7/2007-2013, HEALTH-F2-2010-259893]
- Netherlands Organization for Scientific Research (NWO)
- Netherlands Genomics Initiative/NWO
- Maurits and Anna de Kock Foundation
- Dutch Cancer Society
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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 degrees 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.
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