Type 2 PIP Kinases Are Potential Therapeutic Targets in Breast Cancer

Phosphatidylinositol-4,5-bisphosphate (PI-4,5-P₂), the principal substrate for phosphoinositide 3-kinase (PI3K), is generated largely by type 1 phosphatidylinositol phosphate (PIP) kinases but can also be produced from PI-5-P at intracellular membranes by the type 2 family of PIP kinases known as phosphatidylinositol-5-phosphate 4-kinases (PI5P4K). The PI5P4Kβ enzyme (encoded by PIP4K2B) has been implicated in cellular stress responses and inhibition of AKT, but the role of PI5P4Ks in tumorigenesis remains unknown. Emerling and colleagues found amplification of PIP4K2B and elevated expression of PI5P4Kα and PI5P4Kβ proteins in a subset of breast tumors, in particular those with ERBB2 amplification or TP53 mutation or deletion. Depletion of both PI5P4Kα and PI5P4Kβ specifically suppressed the proliferation of HER2-positive, TP53-mutant breast cancer cells and impaired xenograft tumor formation; this growth-inhibitory phenotype was dependent on loss of p53 function and was associated with accumulation of reactive oxygen species (ROS) and induction of senescence. In addition, p53-deficient but not p53–wild-type breast cancer cells exhibited increased oxygen consumption and reduced glycolysis in the absence of PI5P4Kα/β, suggesting that these enzymes promote glucose metabolism to protect against oxidative stress and ROS-triggered senescence in the context of p53 loss. Of note, PI5P4Kα/β depletion paradoxically increased PI3K/AKT signaling despite reducing glucose metabolism, and inhibition of AKT did not reduce ROS production or prevent senescence. Intriguingly, germline deletion of PIP4K2B in the absence of TP53 did not yield viable offspring, supporting overlapping roles of p53 and PI5P4Kβ in cellular stress responses. In contrast, deficiency of both PIP4K2A (encoding PI5P4Kα) alleles and one allele of PIP4K2B diminished spontaneous tumor formation in TP53-null mice without affecting viability. These results identify a role for type 2 PIP kinases in regulating metabolism in response to ROS stress and suggest that PI5P4K inhibitors may be effective in TP53-mutant breast tumors.

Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R, Wulf GM, et al. Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors. Cell 2013;155:844–57.