PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer

Robert J. Crowder, Chanpheng Phommaly, Yu Tao, Jeremy Hoog, Jingqin Luo, Charles M. Perou, Joel S. Parker, Melinda A. Miller, David G. Huntsman, Li Lin, Jacqueline Snider, Sherri R. Davies, John A. Olson, Mark Watson, Anthony Saporita, Jason Weber, Matthew J. Ellis

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168 Scopus citations

Abstract

Several phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)-positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110αand p110β, in ER + breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110αRNAi inhibited growth and promoted apoptosis in all tested ER + breast cancer cells under estrogen deprived-conditions, whereas p110βRNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110α/p110βinhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER + breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110αand p110βcatalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER + breast cancer.

Original languageEnglish
Pages (from-to)3955-3962
Number of pages8
JournalCancer research
Volume69
Issue number9
DOIs
StatePublished - May 1 2009

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    Crowder, R. J., Phommaly, C., Tao, Y., Hoog, J., Luo, J., Perou, C. M., Parker, J. S., Miller, M. A., Huntsman, D. G., Lin, L., Snider, J., Davies, S. R., Olson, J. A., Watson, M., Saporita, A., Weber, J., & Ellis, M. J. (2009). PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer research, 69(9), 3955-3962. https://doi.org/10.1158/0008-5472.CAN-08-4450