Joint success in rare gastrointestinal cancer

How can gastrointestinal stromal tumors (GIST) be treated and new therapies developed? For more than ten years, oncologists in Essen and drug researchers in Dortmund have been battling the rare gastrointestinal cancer GIST. The latest results of their long-standing collaboration have now been published in the Journal of Clinical Oncology and in Nature Communications.

Under the leadership of Prof. Bauer, the researchers were able to identify a completely new form of resistance mechanism that explains why patients suffering from GIST no longer respond to the latest therapies. This work is an important prerequisite for the development of new therapies.

The second study, led by Prof. Rauh, deals with the binding mode of the newly approved drug avapritinib, for which resistance mutations have already occurred after a short time. The study provides important findings for the development of innovative active substances that can circumvent this resistance.

Both publications are the result of close cooperation between the oncologists in Essen and the drug researchers in Dortmund. While Prof. Bauer and his team primarily work clinically and are therefore very close to GIST patients and develop genetic tumor models that can be used to investigate drug resistance, Prof. Rauh's team focuses on the molecular causes of these resistance mutations. Using X-ray structure analyses and preparative organic synthesis, the researchers are developing targeted active substances that are able to circumvent resistance in GIST and thus provide new starting points for the development of future drugs.

The joint work has made a significant contribution to understanding the molecular mechanisms behind the resistance mutations in GIST, thus enabling the development of new approaches to overcome them.

The research work was supported by the German Research Foundation (DFG), the Drug Discovery Hub Dortmund (DDHD), the NRW program "Networks 2021" (CANTAR) and the Mercator Research Center Ruhr (IGNITE).

Original publications:

KIT ATP-Binding pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape. Mühlenberg, T., Falkenhorst, J., Schulz, T. et al. J Clin Oncol. 2024 Feb 26:JCO2301197.

Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA. Teuber, A., Schulz, T., Fletcher, B.S. et al. Nat Commun.2024: 15, 63.

Source: DKTK