RT Journal Article
SR Electronic
T1 Aberrant BCMA Signaling Promotes Tumor Growth by Altering Protein Translation Machinery, a Therapeutic Target for the Treatment of Relapse/Refractory Multiple Myeloma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.03.442500
DO 10.1101/2021.05.03.442500
A1 Yu Rebecca Miao
A1 Can Cenik
A1 Dadi Jiang
A1 Kazue Mizuno
A1 Grace Caiyun Li
A1 Hongjuan Zhao
A1 Kaushik Thakker
A1 Anh Diep
A1 Jimmy Yu Xu
A1 Xin Eric Zhang
A1 Michaela Liedtke
A1 Parveen Abidi
A1 Wing-sze Leung
A1 Albert C. Koong
A1 Amato J. Giaccia
YR 2021
UL http://biorxiv.org/content/early/2021/05/04/2021.05.03.442500.abstract
AB B-cell maturation antigen (BCMA) is critical for the viability of Multiple Myeloma (MM) tumor cells and targeting BCMA poses a remarkable opportunity as a potential therapeutic in this cancer. Recent approval of BCMA directed CAR-T and Antibody-Drug-Conjugates (ADCs) have revolutionized MM treatment landscape. Despite such clinical success, treatment resistance and dose limiting toxicity remain as major clinical challenges. Using ribosome profiling, we established a molecular link between BCMA signaling inhibition and protein translation machinery. In addition, BCMA signaling alters the translation efficiency of a transcriptional regulator ATMIN without changing the total mRNA transcript level. Furthermore, ATMIN can transcriptionally regulate IL-6, a critical survival factor for MM. To inhibit the BCMA signaling pathway, we devised both genetic knockdown strategy and pharmacological inhibition by using a soluble BCMA decoy receptor fusion protein (sBCMA-Fc) to trap both of its ligands, APRIL and BAFF. We demonstrated that treatment of MM tumor cells with sBCMA-Fc inhibits tumor progression in numerous in vivo and syngenic PDX tumors models without significant adverse effects. Furthermore, the addition of sBCMA-Fc treatment can restore bortezomib sensitivity in previously bortezomib resistant MM tumors, further adding to its therapeutic value in the treatment of relapse /refractory MM patients. Inhibiting BCMA signaling through neutralization of its ligands APRIL and BAFF with a sBCMA-Fc fusion protein represents a safe and efficacious treatment strategy for the treatment of relapse and refractory MM.One Sentence Summary B-Cell Maturation Antigen is a regulator of protein translation machinery in Multiple Myeloma and can be safely targeted as a treatment for relapse/refractory Multiple Myeloma.Competing Interest StatementThe authors have declared no competing interest.