AsianScientist (Dec. 10, 2020) – By mapping the mutations associated with common cancers, scientists from Singapore have identified a biomarker that could help predict which patients will respond to certain cancer therapies. Their findings were published in Cancer Research.
Within our bodies, complex signalling pathways orchestrate various biological processes by enabling communication between neighboring cells. The Wnt pathway, for instance, is implicated in cell and organ development as well as tissue regeneration. However, an excess of Wnt proteins is also associated with several common cancers. As many mutations can trigger excessive Wnt activity, finding reliable biomarkers for Wnt-associated cancers is a challenge.
In this study, researchers led by Assistant Professor Babita Madan from Duke-NUS Medical School, along with collaborators from Erasmus University Medical Center, Yale-NUS College and Duke University, profiled 164 RNF43 mutations associated with various human cancers.
Madan and her team found that many of the RNF43 mutations found in patients caused the gene to lose its function. A known tumor suppressor gene, RNF43 typically inhibits Wnt signaling. Therefore, when patients lack functional RNF43, Wnt receptors effectively go into hyperdrive—causing cancer in the process.
To see whether cancers with RNF43 mutations would respond to drugs under development, the researchers tested the small molecule drug candidate ETC-159 in mice implanted with patient-derived tumor tissue. ETC-159, notable for being Singapore’s first publicly funded drug candidate, inhibits enzymes that play a critical role in activating the Wnt pathway.
“It has been shown in the past that RNF43 regulates cell surface Wnt receptors,” noted first author Dr. Yu Jia. “RNF43 mutations could cause sensitivity to Wnt inhibitors in pancreatic cancers.”
True enough, the team found that cancers with RNF43 mutations had more Wnt receptors at the cell surface and were therefore more sensitive to Wnt inhibitors like ETC-159.
Ultimately, the team’s study shows that RNF43 is a promising biomarker for Wnt-associated cancers. Their findings could potentially allow clinicians involved in trials for Wnt inhibitors to easily identify which patients would best respond to treatment based on the mutations present.
“This is another major step towards bringing personalized medicine to cancer patients in Singapore and across the globe,” commented Professor Patrick Casey, Senior Vice-Dean of Research at Duke-NUS. “Being able to customize treatments to the unique genetic signature of a patient’s cancer will allow healthcare providers to better customize treatment plans and greatly increase the chance of real impact on the disease.”
The article can be found at: Yu et al. (2020) The Functional Landscape of Patient-derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition.
Source: Duke-NUS Medical School; Photo: Shutterstock.
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