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 and Sang Hyun Lee ()
Additional contact information
Mayumi Kitagawa: Duke-NUS Medical School
Pei-Ju Liao: Duke-NUS Medical School
Kyung Hee Lee: Duke-NUS Medical School
Jasmine Wong: Duke-NUS Medical School
See Cheng Shang: National University of Singapore
Noriaki Minami: Keio University School of Medicine
Oltea Sampetrean: Keio University School of Medicine
Hideyuki Saya: Keio University School of Medicine
Dai Lingyun: Nanyang Technological University
Nayana Prabhu: Nanyang Technological University
Go Ka Diam: Nanyang Technological University
Radoslaw Sobota: A*STAR
Andreas Larsson: Nanyang Technological University
Pär Nordlund: Nanyang Technological University
Frank McCormick: UCSF Helen Diller Family Comprehensive Cancer Center
Sujoy Ghosh: North Carolina Central University
David M. Epstein: Duke-NUS Medical School
Brian W. Dymock: National University of Singapore
Sang Hyun Lee: Duke-NUS Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02287-5

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