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

Przemek M. Krawczyk; Berina Eppink; Jeroen Essers; Jan Stap; Hans Rodermond; Hanny Odijk; Alex Zelensky; Chris van Bree; Lukas J. Stalpers; Marrije R. Buist; Thomas Soullié; Joost Rens; Hence J. M. Verhagen; Mark J. O'Connor; Nicolaas A. P. Franken; Timo L. M. ten Hagen; Roland Kanaar; Jacob A. 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

Przemek M. Krawczyk
, Berina Eppink
, Jeroen Essers
, Jan Stap
, Hans Rodermond
, Hanny Odijk
, Alex Zelensky
, Chris van Bree
, Lukas J. Stalpers
, Marrije R. Buist
, Thomas Soullié
, Joost Rens
, Hence J. M. Verhagen
, Mark J. O'Connor
, Nicolaas A. P. Franken
, Timo L. M. ten Hagen
, Roland Kanaar
, Jacob A. Aten

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

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

Original language	English
Pages (from-to)	9851-9856
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	24
DOIs	https://doi.org/10.1073/pnas.1101053108
Publication status	Published - 2011

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10.1073/pnas.1101053108

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Krawczyk, P. M., Eppink, B., Essers, J., Stap, J., Rodermond, H., Odijk, H., Zelensky, A., van Bree, C., Stalpers, L. J., Buist, M. R., Soullié, T., Rens, J., Verhagen, H. J. M., O'Connor, M. J., Franken, N. A. P., ten Hagen, T. L. M., Kanaar, R., & Aten, J. A. (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 United States of America, 108(24), 9851-9856. https://doi.org/10.1073/pnas.1101053108

@article{de69ffe1c60b4de287dd5e79435d595c,

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",

author = "Krawczyk, \{Przemek M.\} and Berina Eppink and Jeroen Essers and Jan Stap and Hans Rodermond and Hanny Odijk and Alex Zelensky and \{van Bree\}, Chris and Stalpers, \{Lukas J.\} and Buist, \{Marrije R.\} and Thomas Soulli{\'e} and Joost Rens and Verhagen, \{Hence J. M.\} and O'Connor, \{Mark J.\} and Franken, \{Nicolaas A. P.\} and \{ten Hagen\}, \{Timo L. M.\} and Roland Kanaar and Aten, \{Jacob A.\}",

year = "2011",

doi = "10.1073/pnas.1101053108",

language = "English",

volume = "108",

pages = "9851--9856",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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, Soullié, T, Rens, J, Verhagen, HJM, O'Connor, MJ, Franken, NAP, ten Hagen, TLM, 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 United States of America, 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, Przemek M.; Eppink, Berina; Essers, Jeroen et al.
In: Proceedings of the National Academy of Sciences of the United States of America, 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, 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 - 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 United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 24

ER -

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

Abstract

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