Proteasome Inhibitor Treatment Repairs Effects of Ribosomal Damage in Multiple Myeloma

Investigators at KU Leuven (Belgium) used high-resolution genomic profiling to examine the consequences of the deletion from chromosomal region 1p22 that is found in 20 to 40% of multiple myeloma (MM) patients. They postulated that the increased virulence of MM in these patients suggested the presence of an unidentified tumor suppressor on the deleted region.

The investigators reported in the December 2, 2016, online edition of the journal Leukemia that they had identified a 58 kilobase minimal deleted region (MDR) on 1p22.1 encompassing two genes: EVI5 (ectopic viral integration site 5) and RPL5 (ribosomal protein L5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases.

RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to the proteasome inhibitor bortezomib. Proteasomes are cellular complexes that break down proteins. In some cancers, the proteins that normally kill cancer cells are broken down too quickly. Bortezomib interrupts this process and lets those proteins kill the cancer cells

In both newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. Although the role of the EVI5 and RPL5 genes in promoting MM progression remains to be determined, the investigators identified RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients.

"The ribosome is the protein factory of a cell. In MM patients, one part of the ribosome is produced less in 20 to 40% of the patients, depending on how aggressive the cancer is. We suspect that their cells are still producing protein, but that the balance is somewhat disrupted. In any case, we found that these people have a poorer prognosis than MM patients with an intact ribosome," said senior author Dr. Kim De Keersmaecker, head of the laboratory for disease mechanisms in cancer at KU Leuven. "One possible treatment for MM is the use of proteasome inhibitors. The proteasome is the protein demolition machine in a cell. There is a type of drugs, including bortezomib, which inhibits its functioning. How the defects in the ribosome influence the proteasome is not quite clear yet. But we discovered that patients with a defective ribosome respond better to bortezomib. In other words, their poorer prognosis can be offset by this treatment. On the basis of these findings, we can now develop tests to identify defects in the ribosome and thus determine which therapy will have most effect in a specific patient."

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