Duke-NUS Medical School scientists have discovered why some pancreatic and colorectal cancers[1] do not respond to Wnt inhibitors, a promising new class of anticancer drugs currently being developed for these cancers. The discovery of him, published in Scientific advances, It not only offers a new cancer therapy target, but also a potential screening tool to identify those patients who will not benefit from this new therapy once it is available.
Many gastrointestinal cancers grow out of control when a mutation puts a key biological pathway that governs cell growth, called Wnt, into hyperdrive. The Wnt pathway is hijacked in this way in more than 80 percent of colorectal cancers and some pancreatic cancers, driving unchecked tumor growth. For this group of patients, drugs that block the Wnt pathway, known as Wnt inhibitors, show great promise and have been at the center of intense scientific study, including at Duke-NUS.[2].
“Although Wnt inhibitors have shown promise in certain patients, our study reveals intrinsic resistance in others,” said Dr. Zhong Zheng, who led the study as a postdoctoral fellow in Duke’s Cancer and Stem Cell Biology Program. NUS. “Understanding the mechanisms behind this resistance is crucial for personalized treatments for patients when drugs do not slow tumor growth at all.”
Focusing on colorectal and pancreatic cancers with an overactive Wnt pathway, Dr Zhong, together with Professor David Virshup, who leads the program at Duke-NUS, used their Wnt inhibitor drug ETC-159, the efficacy of which had been established in preclinical models, to evaluate the responsiveness of cancer cells.
By analyzing genetic data from responding and non-responsive tumors, they discovered that a second mutation in another gene, known as FBXW7, makes cancer cells stubbornly resistant to Wnt-blocking drugs.
FBXW7 mutations occur in about 15 percent of colorectal cancers. “FBXW7 mutations change the personality of cancer,” explained Dr. Zhong. “They no longer ‘care’ about the Wnt pathway and therefore the drugs can no longer do their job.”
Testing tumors for FBXW7 gene mutations could prevent many patients from receiving ineffective treatment, making it not only a potential biomarker but also a target for a new type of cancer treatment.
“Predicting drug resistance is critical for precision oncology,” said senior author Professor Virshup. “This work reveals how cancers can evade dependence on Wnt signaling and serves as a solid foundation for further development.”
“We can now try to target the backup pathways activated by the FBXW7 mutation to overcome drug resistance,” Dr. Zhong added, pointing to new treatment possibilities.
The findings add to scientists’ previous work on how pancreatic cancers become resistant to treatment. Together, these discoveries increase our understanding of the ways in which cancers find alternative routes to grow and survive.
With more precise therapeutic goals to target, these findings bring the promise of personalized therapies one step closer to reality. In addition to the discovery of FBXW7, the team discovered that these Wnt inhibitor-resistant tumors were susceptible to an experimental drug known as dinaciclib. Their next step is to investigate the potential of dinaciclib alone and in combination with other agents for the treatment of these cancers.
“Our ultimate goal is to help patients with fully resistant tumors by focusing on alternative cancer pathways triggered by FBXW7 mutations,” said Professor Virshup. “We hope to translate our findings into more powerful and personalized treatment strategies.”
“This research exemplifies the highly translational nature of basic science research conducted at Duke-NUS. Cancers are notoriously diverse, and it is important that we can understand and map that diversity, so that we can offer truly personalized treatment that is effective for the individual.” and not letting patients undergo unnecessary therapies that won’t work for them,” said Professor Patrick Tan, Senior Vice Dean for Research at Duke-NUS. “This study is another important step in our path to making every cancer a treatable disease and the team exemplifies our determination to bring more effective therapies to patients.”
[1] Colorectal cancers are the second most common type of cancer diagnosed in Singapore for both men and women. Pancreatic cancer is 10th most common cause of cancer in men in Singapore. The World Health Organization estimated that more than 1.9 million new cases of colorectal cancer were diagnosed worldwide in 2020 alone.
[2] Duke-NUS, together with A*STAR, developed a Singapore-made Wnt inhibitor called ETC-159 that is currently in early-phase clinical trials.