Mechanisms of resistance to therapies targeting BRCA-mutant cancers

CJ Lord, A Ashworth - Nature medicine, 2013 - nature.com
CJ Lord, A Ashworth
Nature medicine, 2013nature.com
Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of
genetic and functional deficiencies in cancers and is now being explored widely. The first
clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors
of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the
BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA
damage. Although this approach has shown promise, multiple potential resistance …
Abstract
Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.
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