PIK3CAandPIK3CBInhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor–Positive Breast Cancer

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, p110A and p110B, in ER + breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110A RNAi inhibited growth and promoted apoptosis in all tested ER + breast cancer cells under estrogen deprived-conditions, whereas p110B RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110A/p110B 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 p110A and p110B 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):3955-62]

An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers

“…7 and Supplementary Fig. 4) [47], as well as a comprehensive list of genes that may constitute amplicon drivers and novel therapeutic targets.…”

“…Interestingly, PAK1 overexpressing luminal breast cancer cell lines have recently been shown to be significantly more sensitive to MEK inhibition [13]. Moreover, the PI3K catalytic subunit inhibitor BEZ235 has been reported to cause selective cell growth inhibition in ER-positive breast cancer cell lines [47] and may constitute an interesting therapeutic approach for subgroups of patients with luminal breast cancer harbouring amplification of these genes.…”

“…4). Protein kinases of these two canonical pathways may constitute targets for therapeutic intervention by PI3K and/or MEK inhibitors [13,46,47]. Luminal breast cancers were also significantly enriched for genes in the networks 'Cell Cycle, Reproductive System Development and Function, Haematological System Development and Function' (score 40) and 'Reproductive System Disease, Cellular Assembly and Organisation, Cellular Movement' (score 33) (Supplementary Tables 11, 12; Fig.…”

Repression of cancer cell senescence by PKCι

“…Mutational activation of PI-3-kinase most frequently occurs as a result of point mutations in the PIK3CA gene, which are found in 25-30% of breast cancers and at a lower frequency in other cancer types (Karakas et al, 2006). Amplification of the PIK3CB gene has also been reported, although this appears to be a relatively rare event (Crowder et al, 2009). All of these events lead to the generation of the second messenger phosphoinositide-3,4,5-trisphosphate on the inner leaflet of the plasma membrane.…”

A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors

“…This strategy would be expected to maximize therapeutic efficacy by enabling administration of appropriate doses and rational drug combinations with other agents, such as androgen receptor antagonists in PTEN-deficient prostate cancer (19)(20)(21), or erbB2 inhibitors and hormonal treatments in breast cancer (22)(23)(24)(25).…”