• Testing for mutations in RNF43, a protein that affects key cancer cell-growth pathway Wnt, gives clinicians actionable insights to tailor treatments better
Researchers from Duke-NUS Medical School, Erasmus University Medical Center, Yale-NUS College and Duke University have found a potential way to predict who will respond to cancer therapies that block Wnt production, such as the novel made-in-Singapore drug ETC-159. This discovery brings the goal of personalised medicine in cancer therapy a step closer to reality.
Wnt proteins are important signalling molecules that help neighbouring cells to communicate with each other. However, when the protein is produced in excess, it causes cancers. Wnt has been implicated as a key driver of many common cancers, including colorectal and breast cancers as well as leukaemia and pancreatic cancer. Many mutations can trigger an excess activity of Wnt, and finding reliable biomarkers has been challenging.
This research, published in Cancer Research, has identified an actionable biomarker—a protein called RNF43—that is altered in a distinct class of Wnt-addicted cancers.
“RNF43 is one instance that can help us predict whether a cancer cell might be dependent on the Wnt pathway,” said Assistant Professor Babita Madan, a research in Duke-NUS’ Cancer and Stem Cell Biology programme and the corresponding author of the study. RNF43 is frequently mutated in colorectal, endometrial, mucinous ovarian, pancreatic and gastric cancers.
The drug ETC-159, which was jointly developed by Duke-NUS and the Agency for Science, Technology and Research, is a novel small molecule drug candidate that targets a subset of colorectal and gynaecological cancers (ovarian and endometrial). It is currently in Phase 1B human trials and was used in this pre-clinical study to determine whether cancers with RNF43 mutations would respond to Wnt inhibitor therapy.
“It has been shown in the past that RNF43 regulates cell surface Wnt receptors and RNF43 mutations could cause sensitivity to Wnt inhibitor in pancreatic cancers,” said Research Fellow Yu Jia, the first author of the study.
This study expands the landscape of actionable RNF43 mutations, opening the door for more patients to benefit from these therapies. Moving forward, the team hopes that their study can help clinicians who are involved in clinical trials for Wnt inhibitors to develop a look-up table based on the team’s list of actionable RNF43 mutations.
“This is another major step towards bringing personalised medicine to cancer patients in Singapore and across the globe,” said Professor Patrick Casey, Senior Vice-Dean of Research at Duke-NUS. “Being able to customise treatments to the unique genetic signature of a patient’s cancer will allow healthcare providers to better customise treatment plans and greatly increase the chance of real impact on the disease.”
Reference: Jia Yu, Permeen Akhtar Bt Mohamed Yuso, Daniëlle T.J. Woutersen, Pamela Goh, Nathan Harmston, Ron Smits, David Epstein, David M. Virshup and Babita Madan (2020). The functional landscape of patient-derived RNF43 mutations predicts sensitivity to Wnt inhibition. Cancer Research. doi: 10.1158/0008-5472.CAN-20-0957