Effect of combining EGFR-targeted therapy and metabolic inhibitors in the treatment of sarcoma — ASN Events
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Effect of combining EGFR-targeted therapy and metabolic inhibitors in the treatment of sarcoma (#163)

Reichelle Yeo 1 , Pierre J. Dilda 1 , Jia-Lin Yang 1
  1. Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia

Current EGFR-targeted therapies have limited effect on the survival outcome of sarcoma, a rare malignant tumour. PENAO, an anti-tumour metabolic compound produced in our laboratory is currently in clinical trials treating various solid tumours; however it has yet to be tested on sarcoma.

Aims: i) Determine the characteristics of PENAO as a single agent and in combination with EGFR-targeted inhibitor gefitinib on sarcoma cell proliferation, ii) identify induced cell death mechanisms, and iii) assess cell metabolism.

Methods: Effects of PENAO and gefitinib treatments as single agents and combination on sarcoma cell proliferation were determined using xCELLigence real-time cell analyser. The combination parameters of the two agents were determined by MTT end-point proliferation assay, followed by CompuSyn software analysis using Chou-Talalay’s method. Cell death mechanisms were investigated by flow cytometry (Annexin-V/Propidium Iodide staining) and Western blotting (cPARP and LC3B detection). Mitochondrial respiration and glycolysis were measured by Seahorse real-time metabolic analyser.

Results: PENAO monotherapy induced anti-proliferation (IC50: 1.1 – 7.3μM) in 6 soft tissue sarcoma (449B, 778, GCT, HT1080, SW872, SW982) and 6 osteosarcoma (143B, HOS, MG-63, Saos-2, SJSA, U2-OS) cell lines. Combination treatment of PENAO and gefitinib had synergistic effects on cell proliferation (CI: 0.52 – 0.73), enhanced cell death and significantly perturbed mitochondrial function of selected soft tissue sarcoma and osteosarcoma cell lines.

Conclusion: Sarcoma cells were sensitive to the combination treatment of PENAO and gefitinib in vitro, synergistically inducing anti-proliferation, significantly enhancing apoptosis and perturbing tumour metabolism. This study supports further in vivo studies and may have immediate impact in translating therapeutic research to clinical trials.