Novel drug target may help overcome resistance to EZH2 inhibitors in SMARCB1-mutated cancers

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EZH2 protein inhibitors are effective against cancers with SMARCB1 mutations such as rhabdoid tumors in children. However, these drugs are prone to treatment resistance. Scientists at St. Jude Children’s Research Hospital have identified a new drug target that may help overcome resistance to EZH2 inhibitors. An article about work appeared today in Molecular cell.

Rhabdoid tumor is a rare cancer that occurs in children. It can develop in the kidneys and soft tissues (malignant rhabdoid tumor) or in the brain (atypical teratoid rhabdoid tumor). These cancers have a characteristic loss of SMARCB1 (a mutation where the gene and the protein it creates are missing).

Previous work by study corresponding author Charles WM Roberts, MD, Ph.D., director of the St. Jude Comprehensive Cancer Center, has shown that EZH2 inhibitors are effective against cancers with SMARCB1 changes. EZH2 is a component of the Polycomb repressive complex, a multi-protein machine that silences gene expression at specific genes.

The EZH2 inhibitor Tazemetostat is approved by the United States Food and Drug Administration (FDA) for cancers with SMARCB1 changes. Roberts’ work inspired further investigations and then clinical trials of the EZH2 inhibitor Tazemetostat, which ultimately led to FDA approval for use in carrier cancers. SMARCB1 changes.

Resistance, where a cancer cell finds a way around the effect of a drug, is a common problem that can render therapies ineffective. In the current study, Roberts’ team investigated the mechanisms used by cancer to resist treatment with the EZH2 inhibitor. Scientists used CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify potential resistance mechanisms.

This study sheds light on how chromatin regulators interact to control transcription. This not only helps us understand this aggressive childhood cancer, but also offers insight into the treatment of cancers with activating mutations in EZH2. »


Charles WM Roberts, MD, Ph.D., Director, St. Jude Comprehensive Cancer Center

Chromatin regulation holds the key

Chromatin is a tightly packed complex of DNA and proteins inside cells. Chromatin must relax to switch genes on and off in tightly regulated processes. Cancers often carry mutations that affect the SWI/SNF chromatin remodeling complex, including loss of SMARCB1 is an example.

The study showed that loss of the chromatin regulator NSD1 caused resistance to the inhibitor EZH2. The researchers showed how NSD1 coordinates transcriptional control and expanded their understanding of the relationship between SWI/SNF and Polycomb. When cancers have a loss of SMARCB1 and are treated with an EZH2 inhibitor, the genes responsible for cell differentiation are reactivated.

“We found that NSD1 is the critical next step after EZH2 inhibition to focus on to make this drug effective and understand how the transcriptional network is activated,” said first author Yiannis Drosos, Ph.D., St. Jude Oncology. Department. “We know that NSD1 does this by placing a very specific mark on chromatin, so we started thinking how can we get around this?”

The researchers found that cells need NSD1 to turn on genes activated by EZH2 inhibition, so loss of NSD1 leads to resistance to EZH2 inhibition. To circumvent the resistance, the scientists turned to a gene that opposes NSD1 function. The researchers showed that the inhibition of this gene, called KDM2Arestored the sensitivity of cancer cells to EZH2 inhibition.

This finding extends beyond rhabdoid tumor to any cancer with loss of SMARCB1, such as certain lymphomas. Currently, there is no KDM2A inhibitor ready for clinical use, but the results could support development by a pharmaceutical company in the future.

The work was part of the St. Jude Collaborative Research Consortium on Chromatin Regulation in Pediatric Cancer. Through collaboration, researchers from different institutions conduct research that requires the expertise of scientists from different specialties to streamline and accelerate progress.

Authors and funding

The study’s authors are Federica Piccioni and David Root, of the Broad Institute of MIT and Harvard; Natarajan Bhanu and Benjamin Garcia, University of Pennsylvania; and Jacquelyn Myers, Beisi Zu, Kaeli Mathias, Emma Beane, Sandi Radko-Juettner, Robert Mobley, Margaret Larsen, Xiaotu Ma, Jonathan Low, Baranda Hansen, Samuel Peters, Sandeep Dhanda, Taosheng Chen, Santhosh Upadhyaya, Shondra Pruett-Miller and Janet Partridge of St. Jude.

The study was supported by grants from the National Cancer Institute (R01CA113794, R01CA172152, R01CA196539, CCSG2P30CA021765, and F31CA261150); CURE AT/RT Now, Garret B. Smith Foundation, and ALSAC, St. Jude’s fundraising and awareness organization.

Source:

Journal reference:

Drosos, Y. et al. (2022) NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon inhibition of EZH2. molecular cell. doi.org/10.1016/j.molcel.2022.04.015.

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