title: Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.
abstract: 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.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Emerling
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Hurov
authors.forename: George
authors.initials: G
authors.lastname: Poulogiannis
authors.forename: Kazumi S
authors.initials: KS
authors.lastname: Tsukazawa
authors.forename: Rayman
authors.initials: R
authors.lastname: Choo-Wing
authors.forename: Gerburg M
authors.initials: GM
authors.lastname: Wulf
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.forename: Hye-Seok
authors.initials: HS
authors.lastname: Shim
authors.forename: Katja A
authors.initials: KA
authors.lastname: Lamia
authors.forename: Lucia E
authors.initials: LE
authors.lastname: Rameh
authors.forename: Gary
authors.initials: G
authors.lastname: Bellinger
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.forename: Andrea
authors.initials: A
authors.lastname: Bullock
authors.forename: Gina M
authors.initials: GM
authors.lastname: Denicola
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Song
authors.forename: Victoria
authors.initials: V
authors.lastname: Brown
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019069:Cell Respiration; D016922:Cellular Senescence; D004622:Embryo, Mammalian / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005804:Genes, Lethal; D064593:Heterografts; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase