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Does Targeting Autophagy Impact the Efficacy of Proteasome Inhibitor Treatment in Myeloma?

By: Vanessa A. Carter, BS
Posted: Wednesday, September 21, 2022

Iris Appelmann, MD, of RWTH Aachen University Hospital, Germany, and colleagues analyzed the efficacy of targeting the IRE1α‐XBP1 axis of the unfolded protein response in multiple myeloma in combination with the proteasome inhibitor ixazomib, since this protein response has shown to be upregulated in this patient population. Published in BMC Cancer, the results of this study suggest that the combined inhibition of autophagy and the proteasome may synergistically induce apoptosis via the stress‐induced JNK pathway in multiple myeloma.

“A comprehensive investigation of alternative pathways contributing to JNK-mediated apoptosis in multiple myeloma for better insight into the specific role of the JNK signaling pathway and its crosstalk with other crucial molecules in response to targeted treatment of multiple myeloma cells remains to be done,” mentioned the study authors. “Hence, we consider the implication of pharmaceutical inhibition of autophagy together with proteasome inhibition and unfolded protein response–directed therapy as a promising novel in vitro treatment strategy against multiple myeloma.”

The German Collection of Microorganisms and Cell Cultures and the Japanese Collection of Research Bank were used to obtain human myeloma cell lines RPMI-8226 and KMS11, respectively, and the RWTH centralized BioMaterialBank (BMB) provided primary bone marrow samples from patients with multiple myeloma. Multiple myeloma cells were treated with ixazomib and small molecule inhibitors (STF‐083010, A106) of IRE1α‐XBP1 and were supplemented with bone marrow mesenchymal stromal cells.

Targeting the axis in combination with ixazomib appeared to induce cell-cycle arrest and a cytotoxic effect in myeloma. Moreover, this combination treatment reduced cell viability in both patient-derived multiple myeloma cells and cell lines. Of note, the aforementioned cytotoxicity mediated by the combined autophagy and proteasome inhibitors seemed to be reversed by the addition of the JNK inhibitor JNK-ln-8, suggesting JNK may be a key mediator in cell apoptosis.

Disclosure: For full disclosures of the study authors, visit

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