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

Ashish Juvekar, Laura N. Burga, Hai Hu, Elaine P. Lunsford, Yasir H Ibrahim, Judith Balmañà, Anbazhagan Rajendran, Antonella Papa, Katherine Spencer, Costas A. Lyssiotis, Caterina Nardella, Pier Paolo Pandolfi, José Baselga, Ralph Scully, John M. Asara, Lewis C Cantley, Gerburg M. Wulf

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239 Citations (Scopus)

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-Cre Brca1 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-ADPribosylation (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.

Original languageEnglish
Pages (from-to)1048-1063
Number of pages16
JournalCancer Discovery
Volume2
Issue number11
DOIs
Publication statusPublished - Nov 2012
Externally publishedYes

Cite this

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, 2(11), 1048-1063. https://doi.org/10.1158/2159-8290.CD-11-0336