Germ-line heterozygosity of the BRCA2 gene in women predisposes to breast and
ovarian cancers. Successful
therapies targeted specifically at these
neoplasms have thus far remained elusive. Recent studies in mice have shown that inhibition of
poly(ADP-ribose) polymerase-1 (PARP-1) targets cells lacking Brca2 and xenografts derived from BRCA2-deficient ES cells or Chinese hamster ovary cells. We set out to develop a more relevant preclinical model that will inform and accelerate translation into the clinic. As such, we conditionally deleted Brca2 and p53 within murine mammary epithelium and treated the resulting
tumors in situ with a highly potent PARP-1 inhibitor (
AZD2281) alone or in combination with
carboplatin. Daily exposure to
AZD2281 for 28 days caused significant regression or growth inhibition in 46 of 52
tumors. This response was shown to be specific to
tumors lacking both Brca2and p53.
AZD2281/
carboplatin combination
therapy for 28 days showed no advantage over
carboplatin monotherapy. However, if
PARP inhibitor treatment was continued, this significantly increased the time to
tumor relapse and death in these mice. This preclinical study is the first to show in vivo
hypersensitivity of spontaneously arising Brca2-deficient mammary
tumors to PARP-1 inhibition monotherapy or combination
therapy. As such, our data add substantial weight to the argument for the use of
PARP inhibitors as therapeutic agents against human breast
cancers in which BRCA2 is mutated. Moreover, the specificity that we have shown further suggests that
PARP inhibitors will be generally effective against
tumors caused by dysregulation of components of the homologous recombination pathway.