Study uncovers the mechanisms behind tumour suppressor BAP1 protein, highlighting new treatment strategies for aggressive cancers

• Tumour suppressor BAP1 protein is implicated in several aggressive cancers, but the mechanisms behind it are not well understood. 
• Scientists from the National Cancer Centre Singapore (NCCS) and Duke-NUS Medical School (Duke-NUS) have uncovered new ways that BAP1 repairs DNA and regulates cell function, leading to promising new therapeutic targets for BAP1-deficient cancers.

Singapore, 2 April 2026 – A team of scientists led by the National Cancer Centre Singapore (NCCS) and Duke-NUS Medical School (Duke-NUS) has found a new approach for treating some of the world's most aggressive cancers associated with BAP1 mutations. Their research, published in the journal Science Translational Medicine on 1 April 2026, uncovers how BAP1 functions at the molecular level and presents a novel therapeutic strategy to slow the progression of mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal cell carcinoma harbouring BAP1 mutations.

BAP1: The cellular quality control supervisor

BAP1 (BRCA-associated protein 1) is a critical tumour suppressor that regulates the cell cycle, DNA repair and cell death. BAP1 oversees proper cellular function much like a quality control supervisor in a factory. When proteins in a cell become damaged, unnecessary or potentially dangerous, they are tagged with ubiquitin. BAP1's job is to check the conveyor belt for specific target proteins that are mistakenly tagged but are still useful, remove their disposal tags through deubiquitination, and put them back to work. When BAP1 is missing or broken, this cellular quality control function is absent and critical proteins needed for DNA repair and cellular function might get destroyed whilst harmful ones remain. This causes cellular chaos, faulty DNA repair and uncontrolled cell division, leading to cancer.

BAP1’s role in cancer development

Deficient BAP1 drives progression in aggressive cancers including mesothelioma (cancer that develops in the thin lining that covers internal organs), uveal melanoma (a type of eye cancer), cholangiocarcinoma (bile duct cancer), and clear cell renal cell carcinoma (the most common type of kidney cancer). The global burden of these BAP1-associated cancers is substantial and growing, with renal cell carcinoma alone affecting more than 400,000 people worldwide each year. Conventional treatments, such as chemotherapy, immunotherapy and radiotherapy, have shown limited success.

While it is known that BAP1 regulates DNA double-strand break repair and helps DNA lesion-repair, exactly how this occurs has been a mystery. Past studies on BAP1 have provided important insights into BAP1 function only in single cancer types, but gaps remain in fully investigating its mechanisms of action and translating these findings into effective therapeutic strategies. Hence, a deeper understanding of BAP1 in cancer biology is crucial for improving outcomes for patients with BAP1-deficient cancers.

Mapping BAP1 and finding new ways to target cancers harbouring BAP1 mutations

To get a clearer understanding of BAP1, the team studied cell lines, organoids, and animal models across the four major BAP1-deficient cancer types: mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal cell carcinoma. Using advanced techniques including mass spectrometry, ChIP sequencing and ATAC sequencing, they discovered that BAP1 plays an important role in global genome nucleotide excision repair (GG-NER), a DNA repair pathway that fixes bulky DNA lesions. They were also able to pinpoint how BAP1 does this, by removing ubiquitin tags from three key DNA damage recognition proteins: DDB1, RAD23B, and COPS7B. This deubiquitinating function protects the proteins from being destroyed, ensuring that they remain available for DNA repair and proper cell function.

The team also conducted comprehensive screening of 422 different anti-cancer drugs to find compounds that could specifically target cancer cells that lack functional BAP1. They discovered that SP2509 (an LSD1 inhibitor), was particularly effective at killing BAP1-deficient cancer cells whilst sparing normal cells. Similarly, Olaparib (a PARP1 inhibitor) proved effective at slowing tumour growth and extending survival in mouse models. When they combined SP2509 with Olaparib, the combination therapy created a powerful synergy that was able to slow cancer cell spread. These findings were validated in laboratory studies, patient-derived organoids (tissue models), and mouse models.

New hope for patients with aggressive cancers

Currently, no approved therapies specifically target BAP1-deficient cancers. Conventional treatments for these cancers show limited effectiveness, with patients displaying variable responses and developing therapeutic resistance. This study provides strong preclinical evidence for a mechanism-based combination strategy, that could potentially address these treatment gaps.

“Understanding how BAP1 works at the molecular level creates new opportunities to test drug combinations that target vulnerabilities in DNA repair. In addition, BAP1 levels and the pathways they influence can serve as biomarkers to better stratify patients, personalise treatment approaches and monitor how effective these treatments are,” said Dr Hong Jing Han, first author of the study and Principal Research Scientist, Cancer & Stem Cell Biology Signature Research Programme at Duke-NUS Medical School.

"We are pleased that our study’s findings offer hope for patients with these historically hard-to-treat BAP1-deficient cancers, by identifying new mechanisms of BAP1 in cancer development and uncovering effective therapeutic strategies. What's particularly encouraging is that the synergistic activity observed when combining LSD1 and PARP1 inhibitors represents a shift from single-drug treatments to more effective, mechanism-based combination strategies," said Professor Teh Bin Tean, Deputy Chief Executive Officer, Venture and Enterprise, National Cancer Centre Singapore. Prof Teh is also from Duke-NUS’ Cancer & Stem Cell Biology Signature Research Programme.

The team now plans to design clinical trials testing LSD1 and PARP1 inhibitors in cancer patients with BAP1 mutations.

Acknowledgements

This research is supported by the Singapore Ministry of Health through the National Medical Research Council (NMRC) Office, MOH Holdings Pte Ltd under the NMRC Singapore Translational Research Investigator Award (MOH-001827 and MOH-000248), as well as the Duke-NUS Medical School (Duke-NUS-KBrFA/2025/0091) and the Tan Yew Oo Distinguished Professorship in Pathology and the Verdant Foundation.

Study citation:

Hong, J. H. et al. (2026). Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pan-cancers. Science Translational Medicine. Advance online publication. https://doi.org/10.1126/scitranslmed.adr6668

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For media enquiries, please contact:

Dharshini Subbiah
Corporate Communications
National Cancer Centre Singapore
Email : dharshini.subbiah@nccs.com.sg 

Alice Chia
Communications
Duke-NUS Medical School
Email: alice.chia@duke-nus.edu.sg

About the National Cancer Centre Singapore (NCCS)

The National Cancer Centre Singapore (NCCS) is a leading national and regional tertiary cancer centre dedicated to advancing cancer care, research and education. With a comprehensive suite of specialties and services, NCCS treats all cancers and offers personalised and multidisciplinary care to ensure that patients receive holistic, compassionate care and support. Advanced and innovative treatments such as proton therapy at the Goh Cheng Liang Proton Therapy Centre, immunotherapy, and cell therapy give patients at NCCS the best treatment outcomes.

Ranked among the top cancer centres in Asia, NCCS is globally recognised for its research expertise, with clinicians and scientists collaborating with local and international partners to conduct cutting-edge clinical and translational research that makes a real impact and offers hope of a cancer-free tomorrow. As an academic healthcare institution, NCCS is committed to nurturing future generations by delivering specialised training to local and overseas oncology healthcare professionals. For more information, please visit www.nccs.com.sg

About Duke-NUS Medical School

Duke-NUS is Singapore’s flagship graduate entry medical school, established in 2005 with a strategic, government-led partnership between two world-class institutions: Duke University and the National University of Singapore (NUS). Through an innovative curriculum, students at Duke-NUS are nurtured to become multi-faceted ‘Clinicians Plus’ poised to steer the healthcare and biomedical ecosystem in Singapore and beyond. A leader in ground-breaking research and translational innovation, Duke-NUS has gained international renown through its five Signature Research Programmes and ten Centres. The enduring impact of its discoveries is amplified by its successful Academic Medicine partnership with Singapore Health Services (SingHealth), Singapore’s largest healthcare group. This strategic alliance has led to the creation of 15 Academic Clinical Programmes, which harness multi-disciplinary research and education to transform medicine and improve lives.

For more information, please visit www.duke-nus.edu.sg