ArticleCancer discovery2012
Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.
Article in Cancer discovery, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 254 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
254 citing papers in PubMed, 1 synthesis or guideline pooled it, 475 citations in OpenAlex.
- Antitumor Activity of s-Triazine Derivatives: A Systematic Review.Molecules (Basel, Switzerland) · 2023Pooled it
- BrUOG360: A Phase Ib/II Study of Copanlisib in Combination with Rucaparib in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC).Cancer research communications · 2025Trial
- Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers.Breast cancer research and treatment · 2025Trial
- Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer.Breast cancer research : BCR · 2020Trial
- Beyond conventional therapies: the evolution of targeted agents and immunotherapies in triple-negative breast cancer.Acta pharmacologica Sinica · 2026Review
- Expanding the therapeutic scope of PARP inhibitors in breast cancer: current indications and future directions.The Journal of clinical investigation · 2026Review
- Insights from three decades of BRCA1/2 modeling in mice.Nature genetics · 2026Review
- The role of the cGAS-STING pathway in male reproductive disorders.Molecular biology reports · 2026Review
- Combination Therapy with Copanlisib and Niraparib in Patients with Recurrent Endometrial and Ovarian Cancer (COPANIRA): Efficacy, Toxicity, and Translational Insights.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Suppression of PARP1 enhances PTEN mRNA therapy in castration-resistant prostate cancer by glycolysis disruption.Molecular therapy. Oncology · 2026Article
- Article
- Simultaneous inhibition of PARP/AKT to intercept nascent BRCA1/2NPJ breast cancer · 2026Article
- Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: Molecular dysregulation, therapeutic advances, and future directions.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Review
- MicroRNA320e Augments the Synthetic Lethality of Olaparib by Regulating the PI3K-AKT-mTOR Pathway.Oncology research · 2026Article
- Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment.bioRxiv : the preprint server for biology · 2025Article
- Article
- Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment.NAR cancer · 2025Article
- Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms.Oncogene · 2025Review
- PARylation-mediated post-transcriptional modifications in cancer immunity and immunotherapy.Frontiers in immunology · 2025Review
- Natural autophagy modulators in non-communicable diseases: from autophagy mechanisms to therapeutic potential.Acta pharmacologica Sinica · 2025Review
194 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
unlabelledThere 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 γ-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. SIGNIFICANCE: 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.