A new study has identified DP103 as a key regulator of Wnt signalling, cancer stemness and treatment resistance in triple-negative breast cancer, and proposes the protein as a diagnostic biomarker to guide precision use of the investigational drug RX-5902.
Researchers at the National University of Singapore (NUS) have identified a potential molecular ‘master switch’ that drives tumour growth and treatment resistance in triple-negative breast cancer (TNBC), one of the most aggressive forms of the disease.
The team found that blocking the regulator, known as DP103, reduced cancer cell growth and spread in laboratory models. The findings also suggest DP103 could potentially serve as a biomarker to identify patients who may benefit from treatment with the investigational drug RX-5902, also known as Supinoxin.
TNBC accounts for around 15 to 20 percent of breast cancers and is associated with a high risk of early recurrence, metastasis and poor survival. Unlike some other breast cancers, it lacks established targeted therapies against common molecular drivers.
Targeting cancer stem cells
The NUS researchers investigated the mechanisms that allow TNBC cells to survive treatment and drive tumour regrowth, focusing on Wnt signalling, a pathway involved in cancer growth and progression.
The researchers identified DP103 as a regulator that helps maintain a self-reinforcing cycle supporting tumour growth, spread and treatment resistance. The protein also helps sustain cancer stem cells, a population of cells that can survive treatment and contribute to recurrence.
The study, published in Cell Death and Disease, combined patient-derived datasets with experiments using human breast cancer cells, three-dimensional tumour models and human tumour organoids.
Across 21 samples, RX-5902 reduced cancer stem cell viability by 40 to 60 percent. Tumour growth in laboratory-grown models fell by approximately 50 percent. 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.
Potential biomarker for precision treatment
“Patients with triple-negative breast cancer are facing an aggressive form of breast cancer with limited treatment options,” said Research Assistant Professor Alan Prem Kumar from the NUS Centre for Cancer Research and Department of Pharmacology, who led the study. ”Our findings suggest that DP103 could potentially serve as a diagnostic biomarker to identify the patients most likely to benefit from RX-5902 treatment, paving the way for a more precise, personalised approach to treating triple-negative breast cancer.”
RX-5902 is an oral targeted therapy designed to interfere with the Wnt/β-catenin pathway. The researchers found that inhibiting this pathway prevented β-catenin from entering the cell nucleus, reducing activation of genes associated with cancer growth and survival.
“The RX-5902 drug is a first-in-class oral targeted therapy designed to block a key cancer-promoting pathway known as Wnt/β-catenin,” added Dr Cai Wanpei, the study’s first author. ”By preventing β-catenin from entering the cell nucleus, the drug switches off genes that drive cancer growth, spread and survival. This slows tumour progression and triggers apoptosis – the natural death of cancer cells.”
Towards clinical validation
“Triple-negative breast cancer remains particularly difficult to treat because standard options such as surgery, chemotherapy and immunotherapy do not work equally well for all patients, and resistance and recurrence are common,” said Associate Professor Celestial Yap, a co-author of the study. ”What makes this finding exciting is that DP103 may represent a new biological vulnerability in the disease, linking tumour growth, stemness and treatment resistance. This discovery offers new insights that could support more precise patient selection and open the door to better targeted strategies for durable disease control and improved clinical outcomes.”
The researchers now plan to validate DP103 as a predictive biomarker in larger patient cohorts and investigate DP103-targeted therapies for potential clinical testing. They will also explore combinations of RX-5902 with existing treatments.
In addition to this, due to the fact that abnormal Wnt signalling is implicated in several other cancers, the researchers say the findings could potentially have applications beyond TNBC and inform new approaches to treating other aggressive tumours.
No comments yet