Mechanism of drug reactivating tumor suppressors

A team of researchers from the University of Tokyo and their colleagues focused on treatments targeting H3K27me3, a modification in the DNA packaging histone protein, which plays a major role in regulating gene expression. Modification occurs when methyl groups, each of which contains three hydrogen atoms, bond to one carbon atom (CH₃) is added to proteins in a process called methylation.

Modifications, also known as epigenetics (a heritable change in gene function that occurs without changing the DNA sequence), are associated with the accumulation of methylated genes to suppress, or reduce the expression of, tumor-suppressor genes. is attached to Histones around the gene.

Because of its gene-suppressing effects, H3K27me3 is being targeted therapeutically to correct some of the aberrant gene expression found in cancer cells. Although this therapy is effective for some cancers, the mechanism of H3K27me3 treatment on tumor cells remains unknown.

The research team conducted a study that identified the effects of H3K27me3 on cancer cells in patients treated with valemetostat for adult T-cell leukemia/lymphoma (ATL), a rare type of blood cancer. are The drug inhibits the methylation of histone H3 by inhibiting the histone-modifying enzymes EZH1 and EZH2, which enhance H3K27 and have been found to be abnormal in cancer. Treatment of patients with valemitostat decreased H3K27me3 and DNA condensation, opening up several tumor suppressor genes for expression in cancer cells.

“Prior to developing H3K27me3-inhibitor therapies, there were no effective treatments for blood cancers with accumulated genetic abnormalities, and new treatments developed need to.” University of Tokyo. “Once we have demonstrated that these treatments are effective against certain types of cancer, understanding the therapeutic mechanisms of these drugs has become extremely important.”

The team established that valmatostat treatment reduced tumor size and produced a durable clinical response to therapy in a clinical trial of patients with ATL, an aggressive cancer with many genetic mutations. Patients were able to stay safely on valmatostat treatment for more than two years.

“In blood cancers with poor prognosis due to genetic abnormalities, epigenetic mechanisms mediated by methylated histones can be therapeutically targeted,” said Professor Kaoru Ichimaru, from the Graduate School of Frontier Sciences. are also the final authors of the study. “Valemetostat can restore the expression of many tumor suppressor genes and permanently inhibit the growth of tumor cells.”

Characterizing the regimen of valemitostat therapy in patients with ATL is a major step toward epigenetic cancer treatments that target gene expression in cancer cells. The team acknowledges, however, that many challenges remain. Cancers can become resistant to H3K27me3-inhibitor therapy if patients are treated for long periods of time, leading to cancer recurrence. In some cases, the cancer cells acquired new mutations that interfered with the effectiveness of valmatostat over time and reduced the patient’s long-term response to the drug.

“EZH1/2 inhibitors are effective treatments, but mechanisms of long-term treatment resistance have also been identified,” Yamagishi said. “Based on this mechanism of resistance, it is important to continue to improve therapeutic approaches and develop combination therapies that provide long-term therapeutic effects.”