NUS researchers identify molecular switch driving TNBC treatment resistance

Discovery of a molecular regulator

Researchers at the National University of Singapore (NUS) have identified a protein, DP103, as a key regulator of treatment resistance in triple-negative breast cancer (TNBC). The findings, published in the journal Cell Death and Disease, suggest that blocking DP103 could reduce tumour growth and spread, and that the protein might serve as a biomarker to guide the use of an investigational drug called RX-5902, also known as Supinoxin.

Triple-negative breast cancer is an aggressive subtype that disproportionately affects women under 40, as reported by The Straits Times and The Star. It is named for its lack of three receptors — oestrogen, progesterone, and HER2 protein — to which standard cancer drugs typically attach. This absence makes the cancer particularly difficult to treat. TNBC accounts for about 15 to 20 percent of breast cancers and is associated with a high risk of early recurrence, metastasis, and poor survival.

The NUS team, from the Yong Loo Lin School of Medicine (NUS Medicine), focused on the Wnt signalling pathway, which controls cell growth and movement. They identified DP103 as a "master regulator" that maintains a self-reinforcing cycle supporting tumour growth, spread, and resistance to treatment, while also sustaining cancer stem cells — a small population of cells that can survive therapy and fuel recurrence.

The drug's effect

The researchers investigated whether RX-5902, an oral targeted therapy designed to interfere with the Wnt/β-catenin pathway, could turn off this master switch. Across 21 samples — including patient tumour tissue, laboratory-grown breast cancer cells, and organoids derived from local cancer patients — the drug reduced cancer stem cell viability by 40 to 60 percent. Tumour growth in laboratory-grown models fell by approximately 50 percent, and in other laboratory models, treatment reduced tumour size by around 90 percent while largely sparing healthy cells.

Treatment also extended survival, with half of the treated models reaching 70 days or more, compared with none of the untreated models. The mechanism, as explained by Cai Wanpei, a PhD student at N2CR and NUS Medicine's pharmacology department during the research, involves preventing beta-catenin from entering the cell nucleus, thereby switching off genes that drive cancer growth.

Potential as a biomarker

DP103 had previously been identified as a biomarker for TNBC by a team led by Alan Prem Kumar. The new study builds on this, suggesting that DP103 levels could help pinpoint patients more likely to benefit from RX-5902. Kumar, the lead researcher, said the study hinted at how to identify those who might respond to the drug, and suggested that future clinical trials could focus on patients with high DP103 levels.

Celestial T. Yap, an associate professor with N2CR and NUS Medicine's physiology department, noted that TNBC remains difficult to treat because conventional treatments may not work for all patients. RX-5902 is already being studied in the treatment of breast cancer.

Next steps

The researchers plan to validate DP103 as a predictive biomarker in larger patient cohorts and investigate therapies that target the regulator directly. They will also explore combining RX-5902 with existing treatments.

Because abnormal Wnt signalling is implicated in several other cancers, the findings could have applications beyond TNBC, potentially opening new avenues in treating other aggressive cancers.