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

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

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.

Highlights

Achieving robust cancer-specific lethality is the ultimate clinical goal
We provide evidence of a mechanism for cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via Rassuppressing PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway, in Ras-pathway activated cancer cells as well as in clinical samples from patients with colorectal and lung adenocarcinomas
Our results provide novel pharmacological strategies against Ras-pathway activated cancers and a mechanism for cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a RasPIK3IP1˧PI3K signaling network, which promises further insight into the role of this signaling network in regulating cross-talk known to drive response and resistance to clinically relevant targeted therapies

Summary

Introduction

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. Our results provide novel pharmacological strategies against Ras-pathway activated cancers and a mechanism for cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a RasPIK3IP1˧PI3K signaling network, which promises further insight into the role of this signaling network in regulating cross-talk known to drive response and resistance to clinically relevant targeted therapies. The difference in GI50 values between normal and cancer cells using MTT assay that measures cell proliferation rate (Fig. 1b, e) is likely underestimated, since a131 preferentially induced cell death in transformed and cancer cells, but not normal cells (Supplementary Fig. 2b), whereas it only arrested normal cells at the G1/S phase of the cell cycle in a transient and reversible manner (Supplementary Fig. 1d) These data suggest that a131 is a potent antiproliferative agent with a clear selectivity toward cancer cells killing. These data indicate that a131 displays a strong selective lethality against Rasactivated or Ras-transformed cells

Methods

Findings

Conclusion