PIK3CA and PIK3CB Inhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor–Positive Breast Cancer

Division of Oncology, Departments of ¹Medicine, ²Biostatistics, and ³Pathology and Immunology, Washington University School of Medicine; ⁴Siteman Comprehensive Cancer Center, St. Louis, Missouri; ⁵Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; ⁶Center for Translational and Applied Genomics and British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and ⁷Duke Comprehensive Cancer Center, Durham, North Carolina

^* To whom correspondence should be addressed. E-mail: mellis{at}dom.wustl.edu.

	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, p110 and p110, in ER⁺ breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110 RNAi inhibited growth and promoted apoptosis in all tested ER⁺ breast cancer cells under estrogen deprived-conditions, whereas p110 RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110/p110 inhibition 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 p110 and p110 catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER⁺ breast cancer. [Cancer Res 2009;69(9):OF1–8]

Key Words: breast cancer, estrogen receptor, PI3K, endocrine therapy, synthetic lethality