Researchers at the Yong Loo Lin School of Medicine at the National University of Singapore have identified a molecular “master switch” that appears to coordinate tumour growth, cancer stem-cell maintenance and treatment resistance in triple-negative breast cancer, one of the most aggressive and difficult-to-treat forms of the disease. The regulator, known as DP103, was found to reinforce the activity of the Wnt/β-catenin signalling pathway, a system that helps control cell renewal during normal development but can become dangerously distorted in cancer. In laboratory experiments, blocking this mechanism with the investigational drug RX-5902, also known as Supinoxin, reduced the ability of tumour cells to grow, survive and spread.
Triple-negative breast cancer accounts for approximately 15 to 20 per cent of all breast cancers. Unlike many other breast tumours, it lacks three commonly used therapeutic targets: the oestrogen receptor, the progesterone receptor and excess human epidermal growth factor receptor 2, or HER2. This means that hormone therapies and HER2-directed drugs are generally ineffective against it, leaving chemotherapy, surgery, radiation and, in selected cases, immunotherapy as the main treatment options. Even when an initial response is achieved, TNBC frequently returns early, spreads to distant organs and develops resistance to treatment. A small subpopulation of tumour cells with stem-like properties is believed to contribute substantially to this cycle of recurrence and metastasis.
Cancer stem cells are not necessarily the most numerous cells in a tumour, but they can have an outsized influence on disease progression. They are capable of self-renewal, can generate different tumour-cell populations and often tolerate conditions that kill more specialised cancer cells. These properties allow them to survive therapy and seed new tumours after treatment. The Singapore-led team investigated the molecular systems that preserve this population in TNBC and focused on Wnt signalling, a pathway that regulates cell fate, tissue regeneration and stem-cell behaviour. When Wnt signalling becomes persistently activated, β-catenin can accumulate and move into the cell nucleus, where it acts with other regulatory proteins to switch on genes associated with proliferation, survival and stemness.
The researchers identified DP103 as a previously unrecognised regulator of this cancer-promoting network. Their findings indicate that DP103 does more than simply participate in the pathway: it helps establish a self-reinforcing molecular circuit that sustains Wnt/β-catenin activity. This circuit appears to preserve the cancer stem-cell state while simultaneously encouraging tumour cells to divide, resist programmed cell death and acquire traits associated with invasion. In effect, DP103 may function as a control point linking several features that make TNBC especially dangerous. Tumours with elevated DP103 activity could therefore be more dependent on this pathway and potentially more vulnerable to drugs designed to interrupt it.
To investigate the mechanism, the team combined patient-derived molecular datasets with experiments in human breast cancer cells, three-dimensional tumour models and human tumour organoids. Unlike conventional two-dimensional cell cultures, organoids and three-dimensional models reproduce aspects of the structure, cellular interactions and spatial conditions found in real tumours. These systems allowed the researchers to examine whether suppressing the DP103-associated pathway could affect tumour behaviour in a setting closer to human disease. Across 21 analysed samples, RX-5902 reduced the viability of cancer stem cells by approximately 40 to 60 per cent. Growth in laboratory-grown tumour models fell by about half, suggesting that the drug was affecting both the stem-like compartment and the broader tumour-cell population.
The drug produced an even more pronounced effect in laboratory animal models. Treatment reduced tumour size by around 90 per cent while largely sparing healthy cells, according to the study. Survival was also extended: half of the treated models reached 70 days or beyond, whereas none of the untreated models achieved that time point. These results suggest that inhibiting the pathway may do more than temporarily slow cell division. By disrupting the molecular conditions that support tumour-cell survival and self-renewal, RX-5902 could potentially weaken the reservoir of cells responsible for regrowth. However, findings from cell cultures, organoids and animal models must still be tested in carefully controlled human clinical trials before the approach can be considered an established treatment.
RX-5902 is described as a first-in-class oral targeted therapy designed to interfere with Wnt/β-catenin signalling. According to the researchers, it prevents β-catenin from entering the cell nucleus. Without nuclear β-catenin, genes that promote uncontrolled growth, metastatic behaviour and cell survival are less effectively activated. The resulting disruption can slow tumour progression and promote apoptosis, the controlled process by which damaged or unnecessary cells are eliminated. This mechanism is particularly significant in TNBC because the disease often relies on overlapping survival programmes, allowing some cells to evade chemotherapy or recover after treatment. Targeting a central pathway regulator could make it more difficult for the tumour to maintain these escape routes.
The findings also raise the possibility that DP103 could serve as a predictive biomarker. A biomarker is a measurable biological feature that helps indicate how a disease is behaving or how a patient may respond to a specific therapy. If further studies confirm that tumours with high DP103 levels are especially dependent on the pathway blocked by RX-5902, testing DP103 could help identify patients most likely to benefit. Such an approach would move treatment away from a one-size-fits-all model and towards molecular selection, in which therapy is matched to the biological vulnerabilities of an individual tumour. The researchers emphasise that this possibility must be validated in larger patient groups and through prospective clinical studies.
The work involved collaborators from the NUS Cancer Science Institute of Singapore, Duke-NUS Medical School, Nanyang Technological University, the National Cancer Centre Singapore, Singapore General Hospital, the Agency for Science, Technology and Research, Rexahn Pharmaceuticals, the University of Edinburgh, the University of Southampton, National Taiwan University and Curtin University. The investigators now plan to evaluate DP103 in larger cohorts and explore combinations of RX-5902 with existing treatments. Combining pathway inhibition with chemotherapy, immunotherapy or other targeted agents could be important because TNBC is biologically diverse and can activate alternative survival mechanisms. The researchers also suggest that DP103-driven Wnt signalling may be relevant beyond breast cancer, since abnormal Wnt activity is implicated in several aggressive tumour types. Their study, published in Cell Death and Disease, provides a potential molecular explanation for how TNBC stemness and resistance are maintained, while offering a route towards more precise therapies for patients facing a disease with limited targeted options.
Subject of Research: DP103 regulation of Wnt/β-catenin signalling, cancer stemness and treatment resistance in triple-negative breast cancer
Article Title: DP103 as a critical modulator of Wnt signaling and cancer stemness: implications for precision treatment in triple negative breast cancer
News Publication Date: 1-Aug-2026
Web References: https://pubmed.ncbi.nlm.nih.gov/42248871/ ; https://doi.org/10.1038/s41419-026-08943-3
References: https://www.nature.com/articles/nrclinonc.2016.66
Image Credits: NUS Yong Loo Lin School of Medicine
Keywords: triple-negative breast cancer, breast cancer, DP103, Wnt signaling, β-catenin, cancer stem cells, RX-5902, Supinoxin, targeted therapy, cancer recurrence, metastasis, precision medicine, tumour organoids
Tags: breast cancer stem-cell maintenance mechanismscancer cell proliferation and metastasis inhibitionDP103 protein in cancerdrug development for triple-negative breast cancerinnovative approaches to difficult-to-treatmolecular master switch in breast cancernew therapeutic targets for aggressive breast cancersrole of molecular regulators in cancer progressionRX-5902 Supinoxin drug in breast cancer treatmenttargeting treatment resistance in triple-negative breast cancertriple-negative breast cancerWnt/β-catenin signalling pathway in tumor growth
