Abstract
PARP1 and PARP2 dual inhibitors, such as olaparib, have been recently FDA approved for the treatment of advanced breast and ovarian cancers. However, their effects on bone mass and bone metastasis are unknown. Here we show that olaparib increases breast cancer bone metastasis through PARP2, but not PARP1, specifically in the myeloid lineage, but not in the cancer cells. Olaparib treatment or PARP1/2 deletion promotes osteoclast differentiation and bone loss. Intriguingly, myeloid deletion of PARP2, but not PARP1, increases the population of immature myeloid cells in bone marrow, and impairs the expression of chemokines such as CCL3 through enhancing the transcriptional repression by β-catenin. Compromised CCL3 production in turn creates an immune-suppressive milieu by altering T cell subpopulations. Our findings warrant careful examination of current PARP inhibitors on bone metastasis and bone loss, and suggest cotreatment with CCL3, β-catenin inhibitors, anti-RANKL or bisphosphonates as potential combination therapy for PARP inhibitors.
Highlights
PARP1 and PARP2 dual inhibitors, such as olaparib, have been recently FDA approved for the treatment of advanced breast and ovarian cancers
The results show that nude mice or BALB/c mice treated with olaparib developed significantly more bone metastases from 1833 cells or 4T1.2 cells, respectively, compared with those treated with DMSO vehicle control, quantified by bioluminescence imaging (BLI; Fig. 1a, b)
We found that the serum levels of a bone resorption marker CTX-1 were significantly elevated in mice injected with PARP2KD cancer cells compared with control cancer cells (Supplementary Fig. 1k, l), indicating increased osteoclast functions in these mice
Summary
PARP1 and PARP2 dual inhibitors, such as olaparib, have been recently FDA approved for the treatment of advanced breast and ovarian cancers. Their effects on bone mass and bone metastasis are unknown. Olaparib treatment or PARP1/2 deletion promotes osteoclast differentiation and bone loss. Blocking osteoclast function by bisphosphonates or RANKL antibody are currently FDA-approved strategies to attenuate metastatic bone disease. These drugs are only at best palliative and do not improve overall patient survival. In 2014, an inhibitor of PARPs, olaparib, was approved by the FDA for treating relapsed BRCA-defective ovarian cancer. Despite the clinical efforts on PARP inhibitors, little is known about the potential roles of PARPs in metastatic bone diseases or the impact of PARP inhibitors on bone metastasis
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