Wnt inhibitors reduce the unfolded protein response and enhance bortezomib-induced cell death in multiple myeloma

Dysregulation of the Wnt pathway is involved in pathogenesis of many types of carcinomas and associated with certain hematological cancers, including multiple myeloma (MM). Several studies reported that MM plasma cells carry a functional Wnt/ß-catenin signaling pathway that promotes cell survival. Despite new and successful treatment options, MM remains incurable due to clinical, genetic and transcriptomic heterogeneity, which ultimately results in therapy resistance and relapse. We examined the therapeutic potential of targeting the Wnt pathway in patient-derived MM cells. Our results demonstrate that inhibition of tankyrase (TNKSi) and inhibition of porcupine (PORCi), two established methods to block the Wnt pathway in other cell types and malignancies, promotes cell death of primary MM cells. Single-cell RNA sequencing showed that inhibition of Wnt signaling is likely effectuated via downregulation of genes involved in the unfolded protein response (UPR). Combining TNKSi and PORCi with bortezomib resulted in a potent killing of primary MM cells, demonstrating that inhibitors of Wnt signaling might be considered as therapeutic targets in future anti-myeloma combinatorial strategies. Overall design: Transcriptome analysis by single-cell RNA sequencing of viable CD38+CD138+ primary MM cells of samples MM09-MM13 after 72 hours of exposure to a combination of 20 µM tankyrase inhibitor (TNKSi) XAV939 and 5 µM porcupine inhibitor C59, or untreated control cells, in the presence of IL-6 and APRIL.