TY - JOUR
T1 - Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer
AU - Juvekar, Ashish
AU - Burga, Laura N.
AU - Hu, Hai
AU - Lunsford, Elaine P.
AU - Ibrahim, Yasir H
AU - Balmañà, Judith
AU - Rajendran, Anbazhagan
AU - Papa, Antonella
AU - Spencer, Katherine
AU - Lyssiotis, Costas A.
AU - Nardella, Caterina
AU - Pandolfi, Pier Paolo
AU - Baselga, José
AU - Scully, Ralph
AU - Asara, John M.
AU - Cantley, Lewis C
AU - Wulf, Gerburg M.
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866709651&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-11-0336
DO - 10.1158/2159-8290.CD-11-0336
M3 - Article
AN - SCOPUS:84866709651
SN - 2159-8274
VL - 2
SP - 1048
EP - 1063
JO - Cancer Discovery
JF - Cancer Discovery
IS - 11
ER -
