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Preclinical evaluation of the PI3K-mTOR dual inhibitor PF-04691502 as a novel therapeutic drug in nasopharyngeal carcinoma

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Summary

Nasopharyngeal carcinoma (NPC) is common in Southeast Asia and over 40 % of NPC tissues have PIK3CA amplification. This study characterized the preclinical activity of a novel potent dual PI3K/mTOR inhibitor, PF-04691502, in five NPC cell lines: CNE-1, HK1, CNE-2, HONE-1 and C666-1, in which all of the cell lines possessed basal and activated expression of Akt and p70S6K. Over 80 % inhibition of cell growth in all of these cell lines were achieved after 72 h of PF-04691502 incubation and their IC50 were in hundred nanomolar range. CNE-2, HK1 and HONE-1 were selected to further evaluate the effect of PF-04691502 on cell cycle, apoptosis and Akt downstream signaling. PF-04691502 induced G0/G1 cell cycle arrest and apoptosis at 24 h incubation and it significantly abrogated Akt and its downstream signaling by suppressing the expression of p-mTOR, p-p70S6K, p-Akt(S473, T308), p-S6 and p-4E-BP1, suggesting its effectiveness in inhibition of translation and protein synthesis. Anti-proliferation was also observed in 3D culture system and spheroids formation of NPC cell line HONE-1-EBV was strongly inhibited by PF-04691502. Antitumor activity was observed in CNE-2 xenograft in 2 weeks of 10 mg/kg PF-09641502 treatment to tumor bearing athymic nude mice. Both tumor volume and weight in treatment group were significantly lower than those in vehicle group while no obvious body weight decrease was found, suggesting this working dose was effective and well-tolerated. Additive effects were observed in combination of PF-09641502 with either cisplatin or paclitaxel. There were no synergistic effect observed in drug combination but PF-09641502 alone was effective in treating cisplatin resistant cell lines as compared to its parental control. The beneficial effects of PF-09641502 in both in vitro and in vivo studies for NPC warrant a further investigation.

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Acknowledgments

This work is supported by an independent research grant from Pfizer. The authors would like to thank The Charlie Lee Charitable Foundation for the generous support of this study.

Conflict of interest

The authors declare that they have no conflict of interest in this study.

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Authors and Affiliations

  1. State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, New Territories, Hong Kong

    Chi Hang Wong, Herbert H. Loong, Connie W. C. Hui, Cecilia P. Y. Lau, Edwin P. Hui, Brigette B. Y. Ma & Anthony T. C. Chan

  2. Department of Clinical Oncology, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China

    Chi Hang Wong

Authors
  1. Chi Hang Wong
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  2. Herbert H. Loong
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  3. Connie W. C. Hui
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  4. Cecilia P. Y. Lau
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  5. Edwin P. Hui
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  6. Brigette B. Y. Ma
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  7. Anthony T. C. Chan
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Corresponding author

Correspondence to Chi Hang Wong.

Additional information

Chi Hang Wong and Herbert H. Loong contribute equally to this work

Findings of this study have been presented as a conference poster in the 2013 American Association for Cancer Research Annual Meeting held in Washington, D.C., USA in March 2013.

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Wong, C.H., Loong, H.H., Hui, C.W.C. et al. Preclinical evaluation of the PI3K-mTOR dual inhibitor PF-04691502 as a novel therapeutic drug in nasopharyngeal carcinoma. Invest New Drugs 31, 1399–1408 (2013). https://doi.org/10.1007/s10637-013-0007-z

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  • DOI: https://doi.org/10.1007/s10637-013-0007-z

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