Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.

Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R, Wulf GM, Bell EL, Shim HS, Lamia KA, Rameh LE, Bellinger G, Sasaki AT, Asara JM, Yuan X, Bullock A, Denicola GM, Song J, Brown V, Signoretti S, Cantley LC
Cell. 2013 155 (4): 844-57

PMID: 24209622 · PMCID: PMC4070383 · DOI:10.1016/j.cell.2013.09.057

Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or β (PI5P4Kα and β) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and β in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K β and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A(-/-), PIP4K2B(+/-), and TP53(-/-) mice were viable and had a dramatic reduction in tumor formation compared to TP53(-/-) littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (17)

Animals Breast Neoplasms Cell Line, Tumor Cell Proliferation Cell Respiration Cellular Senescence Embryo, Mammalian Gene Knockdown Techniques Genes, Lethal Heterografts Humans Mice Neoplasm Transplantation Phosphotransferases (Alcohol Group Acceptor) Reactive Oxygen Species Signal Transduction Tumor Suppressor Protein p53

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