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Development of novel inhibitors targeting oncogenic signaling in TKI-resistant gastrointestinal stromal tumors

Subject Area Hematology, Oncology
Organic Molecular Chemistry - Synthesis and Characterisation
Term from 2014 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 258480180
 
Final Report Year 2023

Final Report Abstract

Gastrointestinal stromal tumors are the most common sarcoma of the gastrointestinal tract and are characterized by activating mutations of the class III receptor tyrosine kinases (RTKs) KIT or PDGFRA. After good initial responses to tyrosine kinase inhibitors (TKIs) such as imatinib or avapritinib targeting these mutated kinases, most patients progress due to resistance mutations in KIT or PDGFRA, respectively. For KIT-driven GIST three further treatment lines exist, which each yield 5-6 months of progression-free survival. After progression through the last approved line of therapy patients die rapidly due to the disease. In this long-standing and still ongoing collaboration, we are dedicated to developing highly potent and specific inhibitors against key mediators of resistance and facilitate their translation into novel clinical treatments in TKI-resistant GIST and other KIT or PDGFRA-driven cancers. Specifically, we set out to: Establish and utilize cell-based compound screens to identify novel lead structures active against therapy-resistant mutant forms of KIT and PDGFRA.  Chemically optimize hit structures for further preclinical development.  Facilitate protein X-ray crystallography and rational design approaches to develop novel inhibitors targeting mutant forms of KIT, PDGFRA, and other cancer-related protein kinases such as EGFR, and HER2. After using CRISPR-Cas9 technology to establish a clinically representative panel of PDGFRA-driven GIST cell lines, we facilitated the RASPELD and COMAS screening units in Dortmund, which specialize in high-throughput compound screening. We screened several kinase-focused compound libraries for growth inhibition in these models to identify novel inhibitors of PDGFRA and KIT. For one screening hit (NDI-1), this has already led to a joint patent application. In addition, we solved the crystal structures of several hits in complex with mutant and wild-type KIT and PDGFR and used this structural information to further optimize the compounds. In an effort to characterize the binding of avapritinib to PDGFRA, we solved the first crystal structures of this innovative drug in complex with PDGFRA and KIT. We used this information to design, synthesize, and characterize avapritinib derivatives to determine key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration. In addition, we identified a unique sub-pocket (Gα pocket) that we are currently exploring for the design of next-generation inhibitors. We have also recently identified a novel mechanism of resistance to the current 4th line therapy for KIT-driven GIST, ripretinib. This extremely potent inhibitor of KIT kinases with secondary mutations in the activation loop of the kinase domain has shown high efficacy in clinical trials in patients with such mutations. However, even these patients eventually become resistant, and we have shown that this is due to tertiary mutations in the ATP-binding pocket of the same KIT protein. We have modeled these mutations in GIST cell lines and have shown that they confer resistance to all drugs currently used or in development for the treatment of GIST, as well as to a broad panel of 55 FDA-approved TKIs. We are currently combining our efforts to overcome these rapidly emerging mutations.

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