PARP Inhibitor Resistance - What Is Beyond BRCA1 or BRCA2 Restoration?

Xu, Guotai; Jonkers, Jos; Rottenberg, Sven (2015). PARP Inhibitor Resistance - What Is Beyond BRCA1 or BRCA2 Restoration? In: Curtin, Nicola J.; Sharma, Ricky A. (eds.) PARP Inhibitor Resistance—What Is Beyond BRCA1 or BRCA2 Restoration? Cancer Drug Discovery and Development: Vol. 83 (pp. 453-471). Cham: Springer International Publishing 10.1007/978-3-319-14151-0_19

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Nearly 10 years ago the usefulness of poly(ADP-ribose) polymerase (PARP) inhibitors to kill BRCA1 or BRCA2-deficient cells was reported, and this finding has served as a prime example of the concept of synthetic lethality in the context of anticancer therapy. The clinical translation of this finding has undergone several ups and downs, however. Despite spectacular responses seen in some patients with BRCA-deficient breast or ovarian cancers, other patients did not show the expected benefit from PARP inhibitor therapy. Thus, like for all novel tailored anti-cancer drugs, upfront and secondary resistance remain major hurdles in the implementation of the initial preclinical finding. We know at least one clinically relevant mechanism of PARP inhibitor resistance: the reversion of BRCA function by secondary mutations. Nevertheless, it is also clear that this mechanism does not explain all cases of resistance. At the moment, we only have a poor understanding of BRCA reversion-independent resistance mechanisms. Preclinical data have pointed in several directions, e.g. increased drug efflux, reduced drug target levels, or alternative DNA repair. Here, we discuss these mechanisms with a focus on potential DNA repair adaptations.

Item Type:

Book Section (Book Chapter)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

600 Technology > 630 Agriculture

ISSN:

2196-9906

ISBN:

978-3-319-14150-3

Series:

Cancer Drug Discovery and Development

Publisher:

Springer International Publishing

Language:

English

Submitter:

Barbara Gautschi-Steffen

Date Deposited:

18 Feb 2016 10:51

Last Modified:

19 Feb 2016 20:29

Publisher DOI:

10.1007/978-3-319-14151-0_19

BORIS DOI:

10.7892/boris.75653

URI:

https://boris.unibe.ch/id/eprint/75653

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