Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-017-02287-5
Title: Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality
Authors: Kitagawa M. 
Liao P.-J. 
Lee K.H. 
Wong J. 
Shang S.C. 
Minami N.
Sampetrean O.
Saya H.
Lingyun D.
Prabhu N.
Diam G.K.
Sobota R.
Larsson A.
Nordlund P.
McCormick F.
Ghosh S. 
Epstein D.M. 
Dymock B.W. 
Lee S.H. 
Keywords: a131
antineoplastic agent
mammalian target of rapamycin
mitogen activated protein kinase
phosphatidylinositol 3 kinase
phosphatidylinositol 5 phosphate 2 kinase
phosphatidylinositol kinase
phosphotransferase inhibitor
protein kinase B
Ras protein
unclassified drug
membrane protein
phosphotransferase
PIK3IP1 protein, human
protein kinase inhibitor
Ras protein
cancer
cells and cell components
enzyme
enzyme activity
growth
inhibition
lipid
animal experiment
animal model
animal tissue
antineoplastic activity
Article
breast cancer
cancer cell
centrosome
controlled study
enzyme activation
female
human
human cell
intracellular signaling
lethality
mitosis
mouse
nonhuman
upregulation
animal
antagonists and inhibitors
Bagg albino mouse
cell proliferation
cell survival
drug effect
drug screening
metabolism
mitosis
neoplasm
nude mouse
signal transduction
tumor cell line
Animals
Cell Line, Tumor
Cell Proliferation
Cell Survival
Female
Humans
Membrane Proteins
Mice
Mice, Inbred BALB C
Mice, Nude
Mitosis
Neoplasms
Phosphotransferases (Alcohol Group Acceptor)
Protein Kinase Inhibitors
ras Proteins
Signal Transduction
Xenograft Model Antitumor Assays
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Kitagawa M., Liao P.-J., Lee K.H., Wong J., Shang S.C., Minami N., Sampetrean O., Saya H., Lingyun D., Prabhu N., Diam G.K., Sobota R., Larsson A., Nordlund P., McCormick F., Ghosh S., Epstein D.M., Dymock B.W., Lee S.H. (2017). Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality. Nature Communications 8 (1) : 2200. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-017-02287-5
Abstract: Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131's ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a RasPI3K signaling network. © 2017 The Author(s).
Source Title: Nature Communications
URI: https://scholarbank.nus.edu.sg/handle/10635/174480
ISSN: 2041-1723
DOI: 10.1038/s41467-017-02287-5
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