2. Academic Validation
  3. Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality

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

  • Nat Commun. 2017 Dec 19;8(1):2200. doi: 10.1038/s41467-017-02287-5.
Mayumi Kitagawa 1,  Pei-Ju Liao 1,  Kyung Hee Lee 1,  Jasmine Wong 1,  See Cheng Shang 2,  Noriaki Minami 3,  Oltea Sampetrean 3,  Hideyuki Saya 3,  Dai Lingyun 4,  Nayana Prabhu 4,  Go Ka Diam 4,  Radoslaw Sobota 5,  Andreas Larsson 4,  Pär Nordlund 4 5 6,  Frank McCormick 7,  Sujoy Ghosh 8 9,  David M Epstein 1 10,  Brian W Dymock 2,  Sang Hyun Lee 11
Affiliations

Affiliations

  • 1 Program in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 2 Department of Pharmacy, National University of Singapore, Singapore, 117543, Singapore.
  • 3 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, 160-0082, Japan.
  • 4 School of Biological Sciences, Nanyang Technological University, Singapore, 138673, Singapore.
  • 5 Institute of Molecular and Cell Biology, A*STAR, Singapore, 138673, Singapore.
  • 6 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, SE-171 77, Sweden.
  • 7 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158-9001, USA.
  • 8 Department of Cardiovascular and Metabolic Research, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA.
  • 9 Program in Cardiovascular and Metabolic Disorders and Centre for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 10 Center for Technology & Development (CTeD), Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 11 Program in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore. sanghyun.lee@duke-nus.edu.sg.
PMID: 29259156 DOI: 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.

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