Dataset Information

Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.

ABSTRACT: There is a need to improve treatments for metastatic breast cancer. Here, we show the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in a MMTV-CreBrca1(f/f)Trp53(+/-) mouse model of breast cancer. When treated with the pan-class IA PI3K inhibitor NVP-BKM120, tumor doubling was delayed from 5 to 26 days. NVP-BKM120 reduced AKT phosphorylation, tumor cell proliferation, and angiogenesis. Resistant tumors maintained suppression of AKT phosphorylation but exhibited activation of the MAPK pathway at the "pushing margin." Surprisingly, PI3K inhibition increased indicators of DNA damage, poly-ADP-ribosylation (PAR), and ?-H2AX, but decreased Rad51 focus formation, suggesting a critical role of PI3K activity for Rad51 recruitment. The PARP inhibitor olaparib alone attenuated tumor growth modestly; however, the combination of NVP-BKM120 and olaparib delayed tumor doubling to more than 70 days in the mouse model and more than 50 days in xenotransplants from human BRCA1-related tumors, suggesting that combined PI3K and PARP inhibition might be an effective treatment of BRCA1-related tumors.Current treatment options for triple-negative breast cancer are limited to chemotherapeutic regimens that have considerable toxicity and are not curative. We report here that the combination of a PI3K inhibitor with a PARP inhibitor provides in vivo synergy for treatment of an endogenous mouse model for BRCA1-related breast cancers, making this a candidate combination to be tested in human clinical trials.

SUBMITTER: Juvekar A

PROVIDER: S-EPMC3733368 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.

Juvekar Ashish A Burga Laura N LN Hu Hai H Lunsford Elaine P EP Ibrahim Yasir H YH Balmañà Judith J Rajendran Anbazhagan A Papa Antonella A Spencer Katherine K Lyssiotis Costas A CA Nardella Caterina C Pandolfi Pier Paolo PP Baselga José J Scully Ralph R Asara John M JM Cantley Lewis C LC Wulf Gerburg M GM

Cancer discovery 20120822 11

<h4>Unlabelled</h4>There is a need to improve treatments for metastatic breast cancer. Here, we show the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in a MMTV-CreBrca1(f/f)Trp53(+/-) mouse model of breast cancer. When treated with the pan-class IA PI3K inhibitor NVP-BKM120, tumor doubling was delayed from 5 to 26 days. NVP-BKM120 reduced AKT phosphorylation, tumor cell proliferation, and angiogenesis. Resistant tumors maintained suppres ...[more]

PMID: 22915751

Similar Datasets

Project description:Poly-ADP-ribose polymerase 1 (PARP-1) and PARP-2 are DNA damage sensors that are most active during S-phase of the cell cycle and that have wider-reaching roles in DNA repair than originally described. BRCA1 and BRCA2 (Breast Cancer) proteins are involved in homologous recombination repair (HRR), which requires a homologous chromosome or sister chromatid as a template to faithfully repair DNA double-strand breaks. The small-molecule NAD+ mimetics, olaparib, niraparib, rucaparib, veliparib, and talazoparib, inhibit the catalytic activity of PARP-1 and PARP-2 and are currently being studied in later-stage clinical trials. PARP inhibitor clinical trials have predominantly focused on patients with breast and ovarian cancer with deleterious germline BRCA1 and BRCA2 mutations (gBRCA1/2+) but are now expanding to include cancers with known, suspected, or more-likely-than-not defects in homologous recombination repair. In ovarian cancer, this group also includes women whose cancers are responsive to platinum therapy. Olaparib was FDA-approved in January 2018 for the treatment of gBRCA1/2+ metastatic breast cancers. gBRCA1+ predisposes women to develop triple-negative breast cancers, while women with gBRCA2+ tend to develop hormone-receptor-positive, human epidermal growth factor receptor 2 negative breast cancers. Although PARP inhibitor monotherapy strategies seem most effective in cancers with homologous recombination repair defects, combination strategies may allow expansion into a wider range of cancers. By interfering with DNA repair, PARP inhibitors essentially sensitize cells to DNA-damaging chemotherapies and radiation therapy. Certainly, one could also consider expanding the utility of PARP inhibitors beyond gBRCA1/2+ cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. Unfortunately, in numerous phase I clinical trials utilizing a combination of cytotoxic chemotherapy at standard doses with dose-escalation of PARP inhibitors, there has generally been failure to reach monotherapy dosages of PARP inhibitors due to myelosuppressive toxicities. Strategies utilizing angiogenesis inhibitors and immune checkpoint inhibitors are generally not hindered by additive toxicities, though the utility of combining PARP inhibitors with treatments that have not been particularly effective in breast cancers somewhat tempers enthusiasm. Finally, there are combination strategies that may serve to mitigate resistance to PARP inhibitors, namely, upregulation of the intracellular PhosphoInositide-3-kinase, AK thymoma (protein kinase B), mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway, or perhaps are more simply meant to interfere with a cell growth pathway heavily implicated in breast cancers while administering relatively well-tolerated PARP inhibitor therapy.

Dataset Information

Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.

Publications

Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets