Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality

Page view(s)
22
Checked on May 22, 2024
Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality
Title:
Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality
Journal Title:
Nature Communications
Keywords:
Publication Date:
19 December 2017
Citation:
Kitagawa, M., Liao, P., Lee, K.H. et al. Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality. Nat Commun 8, 2200 (2017). 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 Ras˧PIK3IP1˧PI3K signaling network.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This research was supported by the National Research Fellow (S.H.L.; NRF-RF2010-02) program, NMRC CBRG (S.H.L.; NMRC/CBRG/0091/2015), NMRC platform funding, MOH (P.N., R.S.; IAFCAT2/004/2015) Young Investigator Grant (R.S.) and the Duke-NUS Medical School (S.H.L.; NUS/RECA(PILOT/2013/0006)).
Description:
ISSN:
2041-1723
Files uploaded:

File Size Format Action
195-s41467-017-02287-5.pdf 2.66 MB PDF Open