The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Combining a PI3K Inhibitor with a PARP Inhibitor Provides an Effective Therapy for BRCA1-Related Breast Cancer
Open accessAbstract
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-CreBrca1f/fTrp53+/− 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. Cancer Discov; 2(11); 1048–63. ©2012 AACR. Read the Commentary on this article by Rehman et al., p. 982. This article is highlighted in the In This Issue feature, p. 961
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1 retracted
BRCA1-induced Apoptosis Involves Inactivation of ERK1/2 Activities
Yan, Y., Haas, J. P., Kim, M., Sgagias, M. K., & Cowan, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201147200 · Cited by 50
RetractedTargeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
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Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
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The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
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Self-citationAudeh, M. W., Carmichael, J., Penson, R. T., Friedlander, M., Powell, B., Bell-McGuinn, K. M., Scott, C., Weitzel, J. N., Oaknin, A., Loman, N., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60893-8 · Cited by 2,279
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Self-citationHickson, I., Zhao, Y., Richardson, C. J., Green, S. J., Martin, N. M. B., Orr, A. I., Reaper, P. M., Jackson, S. P., Curtin, N. J., & Smith, G. C. M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2727 · Cited by 1,220
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Cited by
The PI3K Pathway in Human Disease
Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017) · Cell · doi:10.1016/j.cell.2017.07.029 · Cited by 2,749
Self-citationThe PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism
Hoxhaj, G., & Manning, B. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0216-7 · Cited by 2,137
State-of-the-art strategies for targeting the DNA damage response in cancer
Pilié, P. G., Tang, C., Mills, G. B., & Yap, T. A. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0114-z · Cited by 1,189
Targeted drug delivery strategies for precision medicines
Manzari, M. T., Shamay, Y., Kiguchi, H., Rosen, N., Scaltriti, M., & Heller, D. A. (2021) · Nature Reviews Materials · doi:10.1038/s41578-020-00269-6 · Cited by 1,183
PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression
Jiao, S., Xia, W., Yamaguchi, H., Wei, Y., Chen, M.-K., Hsu, J.-M., Hsu, J. L., Yu, W.-H., Du, Y., Lee, H.-H., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3215 · Cited by 981
Metadata
- Authors
- Juvekar, A., Burga, L. N., Hu, H., Lunsford, E. P., Ibrahim, Y. H., Balmañà, J., Rajendran, A., Papa, A., Spencer, K., Lyssiotis, C. A., Nardella, C., Pandolfi, P. P., Baselga, J., Scully, R., Asara, J. M., Cantley, L. C., & Wulf, G. M.
- Venue
- Cancer Discovery
- Published
- 2012-11-01
- Volume
- 2
- Issue
- 11
- Pages
- 1048-1063
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2120806256
- Cited by
- 465
- References
- 48
- FWCI
- 15.34
- Type
- journal article
- Language
- en
- Open access
- green
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- Juvekar, A., Burga, L. N., Hu, H., Lunsford, E. P., Ibrahim, Y. H., Balmañà, J., Rajendran, A., Papa, A., Spencer, K., Lyssiotis, C. A., Nardella, C., Pandolfi, P. P., Baselga, J., Scully, R., Asara, J. M., Cantley, L. C., & Wulf, G. M. (2012). Combining a PI3K Inhibitor with a PARP Inhibitor Provides an Effective Therapy for BRCA1-Related Breast Cancer. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-11-0336
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