Exploration of Autophagy in BAP1-deficient Tumors: UDE Researchers Identify Promising Therapeutic Strategy
In a groundbreaking discovery, researchers at the University Hospital Essen have identified a potential new treatment strategy for aggressive tumors with BAP1 mutations, such as uveal melanoma and kidney cancer.
Dr. Samuel Peña-Llopis, head of the translational genomics working group in the clinic for ophthalmology, and Dr. Silvia Vega Rubin de Celis, head of the autophagy in cancer group at the Institute for Cell Biology (tumor research), led the study. The researchers' work was recently published in the renowned journal "Autophagy" and is titled "Autophagy suppression via SRC induction represents a therapeutic vulnerability for BAP1-mutant cancers".
The study revealed that BAP1 mutations activate the proto-oncogene SRC and disrupt autophagy, the cell's self-cleaning process. This finding is significant as it suggests that targeting both SRC and autophagy could be an effective treatment approach for BAP1-deficient tumors.
The researchers tested the combination of SRC inhibitors, such as Dasatinib and Saracatinib, and autophagy-inducing drugs, such as Tat-BECN1 and SW076956, in laboratory experiments and tumor organoids. The results showed promising synergistic effects, particularly in the absence of BAP1.
While direct clinical or preclinical evidence demonstrating the effectiveness of this combination in BAP1-deficient tumors is not currently available, the researchers' findings provide a strong rationale for further investigation. The combination of kinase inhibitors and autophagy inducers is a new personalized approach to treating BAP1-deficient tumors.
The researchers are now aiming to further develop this strategy to initiate clinical studies. The combination therapy has already been patented (WO2025056601).
The study was funded by the German Cancer Aid, DKTK, Horizon 2020 research and innovation program of the European Union, German Research Foundation (DFG), research focus program "Translational Oncology" of the German Cancer Aid, IFORES, and Josepha and Charlotte von Siebold Habilitandinnen funding program of the University of Duisburg-Essen.
Single-target therapies, including epigenetic or signaling pathway inhibitors, often have limited effects alone. Combination approaches are more promising in overcoming cancer resistance. Autophagy modulation plays a significant role in tumor progression and therapy response. For example, autophagy can promote or inhibit cancer depending on context, and targeting autophagy pathways can suppress tumor growth in renal cancers. SRC kinases are important oncogenic drivers in multiple cancers, and SRC inhibitors have been explored extensively; however, details on their combined use with autophagy modulators in BAP1-deficient tumors are not explicit in these results.
Preclinical studies outside these search results have suggested that BAP1 deficiency may sensitize tumors to disruptions in cellular stress responses including autophagy and SRC signaling, providing a rationale for combination treatment.
In conclusion, while the concept of combined SRC inhibitors and autophagy-inducing drugs is mechanistically rational for targeting BAP1-deficient uveal melanoma and kidney cancer, direct clinical or preclinical evidence demonstrating effectiveness is not currently available in these search results. However, the researchers' findings provide a strong rationale for further investigation, and combination therapies targeting multiple pathways are generally more promising than single agents. Further focused studies or trials are needed to establish this combination’s therapeutic value in BAP1-deficient tumors.
In light of the researchers' findings indicating that BAP1 mutations can activate SRC and disrupt autophagy, a potential new treatment strategy for BAP1-deficient uveal melanoma and kidney cancer could involve targeting both SRC and autophagy, as shown by the promising synergistic effects of combination therapies using SRC inhibitors and autophagy-inducing drugs. Furthermore, the current study suggests that autophagy modulation plays a significant role in tumor progression and therapy response for such medical-conditions as cancer, including renal cancers, underscoring the importance of continuing to investigate this health-and-wellness issue.
