Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for a mouse model of BRCA1-related breast cancer
Menées à l'aide de modèles murins et de xénogreffes, ces deux études suggèrent l'efficacité d'un traitement combinant un inhibiteur de PARP et un inhibiteur de PI3K dans les cancers du sein triplement négatifs ou présentant une mutation de BRCA1
There is a need to improve treatments for metastatic breast cancer. Here we show activation of the phosphoinositide 3-kinase (PI3K) and MAP kinase (MAPK) pathways in a MMTV-CreBRCA1f/fp53+/- 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 and γH2AX, but decreased Rad51 focus formation, suggesting a critical role of PI3K activity for Rad51 recruitment. 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 over 50 days in xenotransplants from human BRCA1-related tumors, suggesting that combined PI3K- and PARP-inhibition might be effective treatment for BRCA1-related tumors.
Cancer Discovery , résumé, 2012