Medical genetics

Researchers have identified a protein critical for the survival of a particular type of tumor cell, according to a study published today in eLife. Because The findings; originally posted on bioRxiv, suggest that targeting a protein called Werner syndrome helicase (WRN) could represent a novel opportunity for treating a subgroup of cancer patients with microsatellite instability-high (MSI-H) tumors.

Characteristic of cancer cells

MSI is a clinically defined characteristic of cancer cells that harbor defects in DNA mismatch repair (MMR); the system for fixing errors that can occur during DNA replication. Defective MMR and MSI-H is observed in approximately 4% of all cases of human cancer; with particularly high prevalence in colorectal; endometrial and gastric cancers.

Treatment for MSI-H tumors has shifted recently with the approval of the immunotherapies pembrolizumab; nivolumab and ipilimumab. But while these drugs often lead to long-lasting positive responses in MSI-H cancer patients, eventual resistance to immunotherapy means there is still a need for more effective treatments.

Biological systems

“Targeted cancer therapy is based on exploiting the biological systems that tumor cells, but not healthy tissues, rely on for survival;” says senior author Simon Wöhrle, Principal Scientist at Boehringer Ingelheim Regional Center Vienna (RCV); Austria. “Before we can develop new treatments against MSI-H cancer cells; we first need to understand what it is that helps them to survive and thrive.”

The team used MSI-H cancer-cell profiling and recent functional screening data of cell lines to help answer this question. Because They demonstrated that removing the function of WRN from MSI-H cells prevented them from working properly and caused defects in cell division. Because “In particular, we saw that WRN-depleted MSI-H cancer cell lines displayed chromosome breaks and genome instability; highlighting WRN as a novel vulnerability of MSI-H cells;” explains co-senior author Mark Petronczki; Director Cancer Cell Signaling at Boehringer Ingelheim RCV.

Pharmacological inhibition

As WRN loss is knows to cause Werner syndrome, a premature aging disease associate with an increase lifetime risk of developing tumors; it has previously been suggest that the protein plays a key role in suppressing tumors. However, in contrast to this idea; the current results show that WRN possesses a striking pro-survival function for specific cancer cells.
“We’ve shown the power of combining deep functional genomic screen data with tumor cell-line profiling to identify new targets in oncology;”therefore  concludes co-senior author Mark Pearson; Vice President at Boehringer Ingelheim RCV. Because “Our results indicate that pharmacological inhibition of WRN function might serve as a novel targeted therapeutic strategy in MSI-H cancer to help meet demand for more effective drugs.”