Antitumor activity of the dual PI3K/mTOR inhibitor gedatolisib and the involvement of ABCB1 in gedatolisib resistance in canine tumor cells

Murase,Yusuke; Hosoya,Kenji; Sato,Takachika; Kim,Sangho; Okumura,Masahiro

doi:10.3892/or.2022.8272

Antitumor activity of the dual PI3K/mTOR inhibitor gedatolisib and the involvement of ABCB1 in gedatolisib resistance in canine tumor cells

Authors:
- Yusuke Murase
- Kenji Hosoya
- Takachika Sato
- Sangho Kim
- Masahiro Okumura
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Affiliations: Laboratory of Veterinary Surgery, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060‑0818, Japan
Published online on: January 27, 2022 https://doi.org/10.3892/or.2022.8272
Article Number: 61
Copyright: © Murase et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The phosphatidylinositol 3‑kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathway is a therapeutic target for various types of human tumors, and dual PI3K/mTOR inhibitors demonstrate antitumor activities in both preclinical and clinical studies. However, resistance mechanisms limit their abilities. As the molecular mechanisms involved in the cellular resistance are not clear in any canine tumors, an understanding of resistance mechanisms would support the potential use of dual PI3K/mTOR inhibitors in canine tumors. The antitumor activity of gedatolisib on cell viability, protein phosphorylation, and cell cycle distribution was assessed using 12 canine tumor cell lines from 6 types of tumors. In addition, the molecular determinants involved in the cellular sensitivity to gedatolisib were explored by investigating the involvement of serum‑and‑glucocorticoid‑induced kinase 1 (SGK1), PIK3CA, and ATP‑binding cassette, subfamily B, member 1 (ABCB1). The results demonstrated that gedatolisib decreased cell viability in all cell lines, with IC₅₀ values <1 µM in 10 of the 12 lines. Gedatolisib inhibited Akt and mTOR complex 1 substrate phosphorylation and induced G₀/G₁ cell cycle arrest. However, certain cell lines with higher IC₅₀ values were more resistant to these effects. These cell lines exhibited higher ABCB1 activity and the ABCB1 inhibitor cyclosporin A enhanced the decrease of cell viability caused by gedatolisib. SGK1 overexpression did not confer resistance to gedatolisib. The mutations of E545K and H1047R in PIK3CA were not observed. The present results indicated that gedatolisib decreased cell viability in canine tumor cell lines and ABCB1 played an important role in gedatolisib resistance, supporting the potential use of gedatolisib for canine tumors.

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