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Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Posted: Friday, February 25, 2022
According to findings presented in EMBO Molecular Medicine, using agents that block the protein complex Sec61 translocon to treat patients with multiple myeloma may improve the efficacy of current chemotherapy and potentially overcome resistance to treatment. Accordign to Caroline Demangel, PhD, of the Université de Paris, France, and colleagues, Sec61 may be a therapeutic vulnerability when treating these patients and possibly other cancer types that need an active Sec61 translocon to survive.
“This study provides the proof of concept that the translocon is a new therapeutic target in multiple myeloma,” the authors stated. “The next step will be to identify drug-like molecules inhibiting Sec61, which could constitute a new treatment for this cancer.”
In this study, the authors used the macrolide mycolactone as a prototypic Sec61 blocker to assess its impact on the cell viability of multiple myeloma. The authors treated three human cell lines (MM.1S, JIM3, and KMS-11) with increasing concentrations of mycolactone for 24 to 72 hours. The induction of cell apoptosis was monitored by phosphatidylserine exposure and the loss of membrane integrity.
In the human cell lines, mycolactone caused rapid defects in the secretion of immunoglobulins and the expression of pr-survival interleukin-6 receptors and CD40. Mycolactone also stimulated proapoptotic endoplasmic reticulum stress responses, synergizing with bortezomib for the induction of multiple myeloma cell deaths and overriding the acquired resistance to the proteasome inhibitor.
Notably, the authors said, the combination of mycolactone and bortezomib rapidly killed patient-derived multiple myeloma cells ex vivo but not as normal mononuclear cells. In immunodeficient mice with multiple myeloma cells, the mycolactone/bortezomib combination demonstrated superior therapeutic efficacy over single-drug treatments without causing toxic side effects, the investigators reported.
Disclosure: The authors reported no conflicts of interest.
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