Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition

PM Krawczyk; Berina Eppink; J. Essers; J Stap; H Rodermond; H Odijk; A Zelensky; C van Bree; LJ Stalpers; MR Buist; Thomas Soullie; Joost Rens; Hence Verhagen; MJ O'Connor; NAP Franken; Timo ten Hagen; Roland Kanaar; JA Aten

doi:10.1073/pnas.1101053108

Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition

PM Krawczyk, Berina Eppink, J. Essers, J Stap, H Rodermond, H Odijk, A Zelensky, C van Bree, LJ Stalpers, MR Buist, Thomas Soullie, Joost Rens, Hence Verhagen, MJ O'Connor, NAP Franken, Timo ten Hagen, Roland Kanaar, JA Aten

Research output: Contribution to journal › Article › Academic › peer-review

292 Citations (Scopus)

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 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.

Original language	Undefined/Unknown
Pages (from-to)	9851-9856
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the U.S.A.
Volume	108
Issue number	24
DOIs	https://doi.org/10.1073/pnas.1101053108
Publication status	Published - 2011

Research programs

EMC COEUR-09
EMC MGC-01-12-03
EMC MM-03-32-04
EMC MM-03-47-11
EMC MM-04-47-07

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.1101053108

http://hdl.handle.net/1765/33400

Cite this

Krawczyk, PM., Eppink, B., Essers, J., Stap, J., Rodermond, H., Odijk, H., Zelensky, A., van Bree, C., Stalpers, LJ., Buist, MR., Soullie, T., Rens, J., Verhagen, H., O'Connor, MJ., Franken, NAP., ten Hagen, T., Kanaar, R., & Aten, JA. (2011). Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proceedings of the National Academy of Sciences of the U.S.A., 108(24), 9851-9856. https://doi.org/10.1073/pnas.1101053108

@article{477f8736a56245858eb15dfac7954ba2,

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 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.",

author = "PM Krawczyk and Berina Eppink and J. Essers and J Stap and H Rodermond and H Odijk and A Zelensky and {van Bree}, C and LJ Stalpers and MR Buist and Thomas Soullie and Joost Rens and Hence Verhagen and MJ O'Connor and NAP Franken and {ten Hagen}, Timo and Roland Kanaar and JA Aten",

year = "2011",

doi = "10.1073/pnas.1101053108",

language = "Undefined/Unknown",

volume = "108",

pages = "9851--9856",

journal = "Proceedings of the National Academy of Sciences of the U.S.A.",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "24",

}

Krawczyk, PM, Eppink, B, Essers, J, Stap, J, Rodermond, H, Odijk, H, Zelensky, A, van Bree, C, Stalpers, LJ, Buist, MR, Soullie, T, Rens, J, Verhagen, H, O'Connor, MJ, Franken, NAP, ten Hagen, T , Kanaar, R & Aten, JA 2011, 'Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition', Proceedings of the National Academy of Sciences of the U.S.A., vol. 108, no. 24, pp. 9851-9856. https://doi.org/10.1073/pnas.1101053108

Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. / Krawczyk, PM; Eppink, Berina; Essers, J. et al.
In: Proceedings of the National Academy of Sciences of the U.S.A., Vol. 108, No. 24, 2011, p. 9851-9856.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition

AU - Krawczyk, PM

AU - Eppink, Berina

AU - Essers, J.

AU - Stap, J

AU - Rodermond, H

AU - Odijk, H

AU - Zelensky, A

AU - van Bree, C

AU - Stalpers, LJ

AU - Buist, MR

AU - Soullie, Thomas

AU - Rens, Joost

AU - Verhagen, Hence

AU - O'Connor, MJ

AU - Franken, NAP

AU - ten Hagen, Timo

AU - Kanaar, Roland

AU - Aten, JA

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 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.

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 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.

U2 - 10.1073/pnas.1101053108

DO - 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 U.S.A.

JF - Proceedings of the National Academy of Sciences of the U.S.A.

IS - 24

ER -