Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma (in research/technical)

Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma | Molecular Cancer Research
December 7, 2016

Abstract

Clear cell ovarian carcinoma (CCOC) is an aggressive form of epithelial ovarian cancer that exhibits low response rates to systemic therapy and poor patient outcomes. Multiple studies in CCOC have revealed expression profiles consistent with increased hypoxia, and our previous data suggests that hypoxia is correlated with increased autophagy in CCOC. Hypoxia-induced autophagy is a key factor promoting tumor cell survival and resistance to therapy. Recent clinical trials with the molecular-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib have demonstrated limited activity. Here, it was evaluated whether the hypoxia-autophagy axis could be modulated to overcome resistance to sunitinib. Importantly, a significant increase in autophagic activity was found with a concomitant loss in cell viability in CCOC cells treated with sunitinib. Pharmacological inhibition of autophagy with the lysomotropic analogue Lys05 inhibited autophagy and enhanced sunitinib-mediated suppression of cell viability. These results were confirmed by siRNA targeting the autophagy-related gene Atg5. In CCOC tumor xenografts, Lys05 potentiated the anti-tumor activity of sunitinib compared to either treatment alone. These data reveal that CCOC tumors have an autophagic dependency and are an ideal tumor histotype for autophagy inhibition as a strategy to overcome resistance to RTK inhibitors like sunitinib. 

Implications: This study shows that autophagy inhibition enhances sunitinib-mediated cell death in a preclinical model of clear cell ovarian carcinoma.

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 Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles, which are sometimes complex.

 

xen·o·graft ˈzenəˌɡraft,ˈzēnə-/ noun plural noun: xenografts

1. a tissue graft or organ transplant from a donor of a different species from the recipient.

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Additional Files

Joyce Deeley Research Centre, BC Cancer Agency, 2410 Lee Ave., Victoria, V8R 6V5, Canada

• Supplemental Figure Legends 1-4 - Supplemental Figure Legends
• Supplemental Figure 1 - IC50 determination for TOV21G, OVTOKO and OVMANA cells following 72 hours of sunitinib.
• Supplemental Figure 2 - Determination of saturating concentrations of Lys05 in CCOC cell lines.
• Supplemental Figure 3 - CCOC cells are more sensitive to Lys05 than HCQ.
• Supplemental Figure 4 - Determination of fraction affected following combination of sunitinib and Lys05.