Understanding EZH2 inhibitor resistance

Inhibitors of the protein EZH2 are effective against cancers with mutations in the SMARCB1 gene. This includes rhabdoid tumors in children. A rhabdoid tumor is a rare cancer in the kidneys and soft tissues or in the brain. Scientists at St. Jude studied how to make EZH2 inhibitors work better.

Resistance is when a cancer cell finds a way around a drug’s effect. It is a common problem that makes targeted therapy ineffective. EZH2 inhibitors experience resistance.

Scientists conducted CRISPR screens in rhabdoid tumor cells with SMARCB1 mutations. They looked for resistance mechanisms and found the cells require the protein NSD1.

Imagine NSD1 puts a mark on the genome. The scientists looked to the gene that erases the NSD1 mark for a solution. The eraser gene, called KDM2A, can be inhibited along with EZH2 to make the drugs more effective.

“This study illuminates how chromatin regulators interact to control transcription,” said Charles W.M. Roberts, MD, PhD, St. Jude Comprehensive Cancer Center director. “It not only helps us understand this aggressive childhood cancer but also offers insight into treating cancers that carry activating mutations in EZH2.”

The findings appeared in Molecular Cell.

Read the news release