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|Title:||Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality||Authors:||Dai, Lingyun
Diam, Go Ka
Epstein, David M.
Dymock, Brian W.
Lee, Sang Hyun
Lee, Kyung Hee
Shang, See Cheng
|Issue Date:||2017||Source:||Kitagawa, M., Liao, P.-J., Lee, K. H., Wong, J., Shang, S. C., Minami, N., et al. (2017). Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality. Nature Communications, 8(1), 2200-.||Series/Report no.:||Nature Communications||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.||URI:||https://hdl.handle.net/10356/87414
|DOI:||10.1038/s41467-017-02287-5||Rights:||© 2017 The Author(s) (Nature Publishing Group). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Journal Articles|
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