The oligosaccharyltransferase complex is an essential component of multiple myeloma plasma cells

TL;DR

The study identifies the oligosaccharyltransferase (OST) complex as a new target for treating multiple myeloma, especially when combined with existing drugs like bortezomib.

Contribution

The OST complex is revealed as a novel therapeutic target in multiple myeloma, with evidence of synergistic effects when inhibited alongside bortezomib.

Findings

Disrupting the OST complex suppresses MM cell growth and induces apoptosis.

OST complex inhibition enhances bortezomib's effectiveness in both in vitro and in vivo models.

OST disruption downregulates key MM pathways like mTORC1 and MYC translation.

Abstract

Multiple myeloma (MM) is an incurable malignancy characterized by mutated plasma cell clonal expansion in the bone marrow, leading to severe clinical symptoms. Thus, identifying new therapeutic targets for MM is crucial. We identified the oligosaccharyltransferase (OST) complex as a novel vulnerability in MM cells. Elevated expression of this complex is associated with relapsed, high-risk MM, and poor prognosis. Disrupting the OST complex suppressed MM cell growth, induced cell-cycle arrest, and apoptosis. Combined inhibition with bortezomib synergistically eliminated MM cells in vitro and in vivo, via suppressing genes related to bortezomib-resistant phenotypes. Mechanistically, OST complex disruption downregulated MM pathological pathways (mTORC1 pathway, glycolysis, MYC targets, and cell cycle) and induced TRAIL-mediated apoptosis. Notably, MYC translation was robustly suppressed upon inhibiting the OST complex. Collectively, the OST complex presents a novel target for MM treatment, and combining its inhibition with bortezomib offers a promising approach for relapsed MM patients.

Tran and colleagues identify the OST complex as a novel vulnerability in MM. The OST complex regulates multiple aspects of myeloma pathology by modulating the mTORC1 pathway and MYC translation. Notably, disrupting the OST complex significantly enhances myeloma cell sensitivity to bortezomib treatment in both in vitro and in vivo models.

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