By Gilang Cahya 
Scientists at Duke-NUS Medical School have made a significant breakthrough in understanding why certain pancreatic and colorectal cancers evade the effects of Wnt inhibitors, a promising new class of drugs in development. Published in the esteemed journal Science Advances, their research not only pinpoints a critical genetic mechanism behind this resistance but also illuminates a novel therapeutic target and a potential screening tool to guide patient treatment. This discovery holds the promise of refining the application of Wnt inhibitor therapies, ensuring that patients receive the most effective treatments and avoiding the administration of drugs that will not yield positive results.
The Wnt Pathway: A Double-Edged Sword in Cancer Growth
The Wnt signaling pathway is a fundamental biological mechanism essential for regulating cell growth, differentiation, and tissue development throughout the body. In healthy cells, this pathway is tightly controlled, acting like a sophisticated dimmer switch that dictates when and how cells should grow and divide. However, in a significant proportion of gastrointestinal cancers, including over 80 percent of colorectal cancers and a subset of pancreatic cancers, this pathway becomes aberrantly activated. Mutations within the Wnt pathway essentially "turn up the dial" to maximum, leading to uncontrolled cell proliferation and the relentless growth of tumors. This hyperactivation makes these cancers particularly vulnerable to drugs designed to inhibit the Wnt pathway, known as Wnt inhibitors.
For years, Wnt inhibitors have been a focal point of intense scientific investigation, including extensive work at Duke-NUS, with the hope of offering a potent new weapon against these devastating diseases. Preclinical models and early-stage clinical trials have shown promising results for some patients, demonstrating the potential of these drugs to significantly slow or even halt tumor progression. However, a persistent challenge has been the observation that a subset of patients, despite having cancers driven by the Wnt pathway, exhibit little to no response to these inhibitors. This intrinsic resistance has posed a major hurdle in realizing the full therapeutic potential of Wnt-targeted therapies.
Unraveling the Mystery of Resistance: The FBXW7 Mutation
The groundbreaking study, led by Dr. Zhong Zheng, a postdoctoral fellow at Duke-NUS’ Cancer & Stem Cell Biology Programme, alongside Professor David Virshup, who heads the Programme, sought to unravel the molecular underpinnings of this observed resistance. Their investigation focused on colorectal and pancreatic cancer cells known to possess a hyperactive Wnt pathway. Employing ETC-159, a Wnt inhibiting drug whose efficacy had been well-established in preclinical models, the research team meticulously assessed the responsiveness of various cancer cell lines and tumor samples.
The critical insight emerged from a detailed analysis of genetic data derived from both responsive and non-responsive tumors. By comparing the genomic profiles, Dr. Zhong and his team identified a recurring genetic anomaly in the resistant tumors: a second mutation in a different gene, known as FBXW7. This discovery was pivotal, revealing that the presence of an FBXW7 mutation fundamentally alters the cancer cells’ susceptibility to Wnt-blocking drugs.
"Although Wnt inhibitors have shown some promise in certain patients, our study reveals intrinsic resistance in others," stated Dr. Zhong. "Understanding the mechanisms behind this resistance is crucial for personalised treatments for patients when the drugs don’t slow tumour growth at all."
The "Personality Change" of Cancer Cells
The FBXW7 gene plays a crucial role in the cell’s "quality control" system, acting as a tumor suppressor by targeting and degrading key proteins involved in cell cycle progression and cancer development. When FBXW7 is mutated, this critical regulatory function is compromised. The researchers found that these FBXW7 mutations effectively "reprogram" the cancer cells, rendering them indifferent to the Wnt pathway’s hyperactivation.
"The FBXW7 mutations change the personality of the cancer," explained Dr. Zhong. "They no longer ‘care’ about the Wnt pathway and so the drugs no longer can do their work." This analogy highlights how the mutation effectively disconnects the cancer’s dependence on the Wnt pathway, making the Wnt inhibitors obsolete in their ability to impede tumor growth. FBXW7 mutations are not an uncommon occurrence, found in approximately 15 percent of colorectal cancers, underscoring the significant clinical implications of this finding.
A Biomarker and a Therapeutic Target: Dual Significance
The identification of FBXW7 mutations as a predictor of Wnt inhibitor resistance carries profound implications for clinical practice. Firstly, it offers a robust biomarker. By testing tumors for the presence of FBXW7 genetic mutations, clinicians can proactively identify patients who are unlikely to benefit from Wnt inhibitor therapy. This diagnostic capability can spare patients from undergoing potentially ineffective and costly treatments, allowing them to pursue alternative therapeutic strategies sooner. This proactive approach aligns perfectly with the principles of precision oncology, ensuring that treatments are tailored to the individual’s specific tumor biology.
Secondly, the discovery of FBXW7’s role opens up new avenues for therapeutic intervention. If FBXW7 mutations lead to resistance by activating alternative survival pathways, then targeting these "backup pathways" becomes a logical next step. This suggests that Wnt inhibitor-resistant cancers might be susceptible to drugs that specifically target these newly activated pathways.
"Predicting drug resistance is critical for precision oncology," emphasized senior author Professor David Virshup. "This work reveals how cancers can evade dependencies on Wnt signalling and serves as a solid foundation for further development."
Dr. Zhong echoed this sentiment, stating, "We can now try to target those backup pathways activated by the FBXW7 mutation to overcome the drug resistance," pointing towards the development of novel combination therapies or entirely new drug classes.
Building on Existing Research: A Continuum of Discovery
This latest research by the Duke-NUS team builds upon their prior work exploring mechanisms of resistance in pancreatic cancers. Their previous studies had also highlighted how these aggressive tumors could find alternative routes for growth and survival when faced with therapeutic challenges. The convergence of these findings significantly deepens the scientific community’s understanding of the multifaceted strategies cancers employ to evade treatment and persist.
The implications of this research extend beyond the immediate discovery. By identifying specific genetic drivers of resistance, scientists are better equipped to develop more precise and effective therapeutic strategies. This move towards highly targeted therapies brings the promise of personalized medicine closer to reality for patients battling complex cancers.
Exploring New Therapeutic Avenues: Dinaciclib and Beyond
In addition to identifying FBXW7 as a resistance mechanism, the study yielded another crucial finding: Wnt inhibitor-resistant tumors, characterized by FBXW7 mutations, demonstrated susceptibility to an experimental drug known as dinaciclib. Dinaciclib is a multi-kinase inhibitor that targets several signaling pathways involved in cancer cell growth and survival. This observation presents an exciting new therapeutic opportunity. The Duke-NUS team’s immediate next step is to rigorously investigate the potential of dinaciclib, both as a standalone treatment and in combination with other agents, for treating these specific types of resistant cancers.
Professor Virshup articulated the ultimate goal: "Our ultimate goal is to help patients with fully resistant tumours by targeting the alternate cancer pathways unleashed by FBXW7 mutations. We hope to translate our findings into more tailored and potent treatment strategies."
Translational Research: The Duke-NUS Ethos
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, highlighted the significance of this research within the institution’s broader mission. "This research exemplifies the highly translational nature of the basic scientific 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 personalised treatment that is effective for the individual and not leave patients to undergo unnecessary therapies that will not work for them."
He further emphasized the impact of such discoveries, stating, "This study is another important step on our journey to make every cancer a treatable disease and the team’s exemplifies our resolve to deliver more effective therapies to patients." This commitment to translating fundamental scientific discoveries into tangible clinical benefits underscores Duke-NUS’s role as a leading institution in cancer research.
Contextualizing the Impact: Cancer Statistics and Global Efforts
The significance of this research is amplified when considering the global burden of colorectal and pancreatic cancers. Colorectal cancer, for instance, is a major public health concern worldwide. In 2020 alone, the World Health Organization estimated that over 1.9 million new cases of colorectal cancer were diagnosed globally. In Singapore, it remains the second most common cancer diagnosed in both men and women. Pancreatic cancer, while less common, is notoriously aggressive and often diagnosed at late stages, making it the 10th most common cause of cancer in men in Singapore. The development of effective therapies for these cancers is therefore of paramount importance.
The Wnt inhibitor ETC-159, utilized in this study, is itself a product of collaborative efforts. It was developed in Singapore by Duke-NUS in partnership with A*STAR, a testament to the nation’s growing strength in biomedical research and innovation. The fact that ETC-159 is already progressing through early-phase clinical trials indicates the rapid pace at which promising laboratory findings are being translated into potential patient treatments.
The identification of FBXW7 as a key resistance mechanism and dinaciclib as a potential therapeutic agent for Wnt inhibitor-resistant cancers represents a significant stride forward. This research not only addresses a critical clinical challenge but also provides a clear roadmap for future drug development and personalized treatment strategies, offering renewed hope to patients facing these formidable diseases. The ongoing pursuit of understanding cancer’s complexity, as exemplified by the Duke-NUS team’s work, is essential in the collective global effort to conquer cancer.
