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

Mayumi Kitagawa; Pei Ju Liao; Kyung Hee Lee; Jasmine Wong; See Cheng Shang; Noriaki Minami; Oltea Sampetrean; Hideyuki Saya; Dai Lingyun; Nayana Prabhu; Go Ka Diam; Radoslaw Sobota; Andreas Larsson; Pär Nordlund; Frank McCormick; Sujoy Ghosh; David M. Epstein; Brian W. Dymock; Sang Hyun Lee

doi:10.1038/s41467-017-02287-5

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

Mayumi Kitagawa, Pei Ju Liao, Kyung Hee Lee, Jasmine Wong, See Cheng Shang, Noriaki Minami, Oltea Sampetrean, Hideyuki Saya, Dai Lingyun, Nayana Prabhu, Go Ka Diam, Radoslaw Sobota, Andreas Larsson, Pär Nordlund, Frank McCormick, Sujoy Ghosh, David M. Epstein, Brian W. Dymock, Sang Hyun Lee

Research output: Contribution to journal › Article › peer-review

63 Citations (Scopus)

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.

Original language	English
Article number	2200
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02287-5
Publication status	Published - 01-12-2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-017-02287-5

Cite this

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), Article 2200. https://doi.org/10.1038/s41467-017-02287-5

@article{6de4c356adcc4598af0714e32aeed2bd,

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

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.",

author = "Mayumi Kitagawa and Liao, {Pei Ju} and Lee, {Kyung Hee} and Jasmine Wong and Shang, {See Cheng} and Noriaki Minami and Oltea Sampetrean and Hideyuki Saya and Dai Lingyun and Nayana Prabhu and Diam, {Go Ka} and Radoslaw Sobota and Andreas Larsson and P{\"a}r Nordlund and Frank McCormick and Sujoy Ghosh and Epstein, {David M.} and Dymock, {Brian W.} and Lee, {Sang Hyun}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-02287-5",

language = "English",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Kitagawa, M, Liao, PJ, Lee, KH, Wong, J, Shang, SC, Minami, N, Sampetrean, O, Saya, H, Lingyun, D, Prabhu, N, Diam, GK, Sobota, R, Larsson, A, Nordlund, P, McCormick, F, Ghosh, S, Epstein, DM, Dymock, BW & Lee, SH 2017, 'Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality', Nature communications, vol. 8, no. 1, 2200. https://doi.org/10.1038/s41467-017-02287-5

TY - JOUR

T1 - Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality

AU - Kitagawa, Mayumi

AU - Liao, Pei Ju

AU - Lee, Kyung Hee

AU - Wong, Jasmine

AU - Shang, See Cheng

AU - Minami, Noriaki

AU - Sampetrean, Oltea

AU - Saya, Hideyuki

AU - Lingyun, Dai

AU - Prabhu, Nayana

AU - Diam, Go Ka

AU - Sobota, Radoslaw

AU - Larsson, Andreas

AU - Nordlund, Pär

AU - McCormick, Frank

AU - Ghosh, Sujoy

AU - Epstein, David M.

AU - Dymock, Brian W.

AU - Lee, Sang Hyun

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85038630273&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038630273&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-02287-5

DO - 10.1038/s41467-017-02287-5

M3 - Article

C2 - 29259156

AN - SCOPUS:85038630273

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2200

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this