Overcoming Innate Resistance to a Beta-Catenin Inhibitor-Tegavivint- by Manipulating Autophagy in Multiple Myeloma

Abstract

Multiple myeloma (MM) is an incurable haematological malignancy with  patients eventually exhausting all available therapeutic modalities and succumbing to the disease. Various lines of evidence have demonstrated that the Wnt/β-catenin pathway is frequently up-regulated in advanced MM. Tegavivint (BC2059), an inhibitor of the Wnt/β-catenin pathway, that we have previously shown to have anti-MM activity  in vitro, ex vivo and in vivo, is currently in clinical trials for the treatment of solid tumours. In this study, we further demonstrate the dose dependent pro-apoptotic activity of BC2059, including activity against the innately resistant human MM cell line (HMCL) LP1. We show that BC2059 causes down-regulation of β-catenin and it’s down-stream target survivin, in parallel with reactive oxygen species (ROS) generation. Coincident with this, BC2059 induces autophagy with a rise in LC3II and fall in p62. Moreover, chemical inhibition of autophagy was highly synergistic with BC2059 in all HMCL tested, with evidence of pro-apoptotic potentiation of BC2059 activity, with enhanced generation of active caspases 8, 9 and 3. Consistent with this, BC2059 treatment of LP1 in combination with knock down of the autophagy related protein Atg5 markedly enhanced cell killing. In conclusion, our results demonstrate that resistance to BC2059 can be partially attributed to the induction of cytoprotective autophagy and that inhibition of autophagy enhances BC2059-induced MM cell killing.  The combination of Wnt/β-catenin pathway and autophagic inhibition represents a novel therapeutic strategy for advanced MM that warrants further evaluation.