Oncotarget

Research Papers:

The synergistic inhibitory effect of combining therapies targeting EGFR and mitochondria in sarcomas

Xiaochun Wang, Reichelle X. Yeo, Philip J. Hogg, David Goldstein, Philip Crowe, Pierre J. Dilda _ and Jia-Lin Yang _

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Oncotarget. 2020; 11:46-61. https://doi.org/10.18632/oncotarget.27416

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Abstract

Xiaochun Wang1,2,*, Reichelle X. Yeo1,3,*, Philip J. Hogg3, David Goldstein4, Philip Crowe1,2, Pierre J. Dilda5 and Jia-Lin Yang1,2

1 Sarcoma and Nano-oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia

2 Department of Surgery, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia

3 The Centenary Institute, NHMRC Clinical Trials Centre, Sydney Medical School, University of Sydney, Sydney, Australia

4 Department of Medical Oncology, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia

5 Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia

* These authors contributed equally to this work

Correspondence to:

Jia-Lin Yang,email: j.yang@unsw.edu.au
Pierre J. Dilda,email: pierre.dilda@biophytis.com

Keywords: EGFR-targeted therapy; mitochondria inhibitor; tumour metabolism inhibition; sarcomas; combination therapy

Received: September 24, 2019     Accepted: December 16, 2019     Published: January 07, 2020

ABSTRACT

Our group previously demonstrated that sarcoma cell lines were insensitive to epidermal growth factor receptor (EGFR) inhibitor gefitinib monotherapy. PENAO, an anti-tumour metabolic compound created in our laboratory, is currently in clinical trials. Considering the positive regulation of tumour energy production by both the EGFR signalling and tumour metabolism pathways, this study aimed to investigate the effect and mechanisms of combination therapy using gefitinib and PENAO in sarcoma cell lines in vitro and in vivo.

PENAO monotherapy reduced proliferation in 12 sarcoma cell lines. Combining gefitinib and PENAO resulted in synergistic inhibition in both a time- and dose-dependent manner in 3 sarcoma cell lines with less prominent monotherapy effects. Combined treatment significantly enhanced cell death and perturbed mitochondrial function. In vivo combination therapy with PENAO and gefitinib was non-toxic to mice and significantly delayed tumour growth and prolonged survival. At 20 days after treatment, tumours from the combination treated mice were significantly smaller than those from untreated and single drug treated mice. The survival curves also showed significant difference across and between groups.

The combination of PENAO and gefitinib in vitro and in vivo, shows promise as a treatment pathway in this poor outcome tumour.


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