Role of Wnt pathway dysregulation in Multiple Myeloma (MM)

MM is a highly heterogeneous and incurable disease. Available evidence suggests that the Wnt/canonical pathway contributes to both disease progression and drug resistance confirming the pathway as an attractive potential therapeutic target. Wnt/β-catenin up-regulation can be the result of multiple factors, which in solid tumour can co-exist, all further enhancing pathway activity. Moreover, we identified a possible additional mechanism relating to the receptor complex expression. Among a variety of Wnt/canonical pathway inhibitors that we tested, BC2059 was shown to have the best anti-MM results in clinically feasible doses, with a favourable in vivo toxicity profile. In the era of combinational chemotherapy BC2059 also proved to exert significant synergistic anti-MM effect both in combination with well-established and novel anti-MM drugs, warranting further investigation. Finally, exploring in more detail the cytotoxic and pro-survival effect of BC2059 we were able to identify that inhibition of autophagy was able to amplify its anti-MM effect. This approach may represent a new paradigm for enhancing the activity of established or novel anti-MM regimens.