Cancer cells can take advantage of the BCL-2 protein to survive chemotherapy, but a drug that suppresses BCL-2 may have promise in patients with leukemia who produce too much of the protein.
Cancer cells may be taking advantage of the BCL-2 protein, which regulates and stops cell death, in order to survive chemotherapy treatment. Researchers in Europe have shown, in a new study published in the journal Leukemia, that a drug suppressing BCL-2 may have promise in patients with leukemia who produce too much of the protein.
The overproduction of BCL-2 is the result of a ribosome defect (RPL10 R98S) and occurs in 8% of pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL).
“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” Kim De Keersmaecker, PhD, head of the Laboratory for Disease Mechanisms in Cancer at KU Leuven, said in a statement. “In the case of a ribosome defect, the cells still produce proteins but the balance between their quantities is slightly off, which leads to cancer.”
She added that cancer cells can use the BCL-2 protein to survive difficult circumstances, including chemotherapy. The researchers used venetoclax, a drug that suppresses BCL-2 and is used to treat chronic lymphocytic leukemia, in mice to suppress T-cell leukemia with a specific ribosome defect.
“These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL,” the authors wrote.
After using the drug, the researchers found an absence of human leukemia cells in the blood of T-ALL xenografted mice. They also observed increased uric acid levels upon development of leukemia in the xenografted mice, suggesting that uric acid levels might indicate mutation in T-ALL cases.
“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”
Kampen KR, Sulima SO, Verbelen B, et al. The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL [published online June 21, 2018]. Leukemia. doi: 10.1038/s41375-018-0176-z.