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

• Applicants: Professor Dr. Sebastian Bauer; Professor Dr. Daniel Rauh
• Subject Area: Hematology, Oncology ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258480180

Gastrointestinal stromal tumors (GIST) are the most common sarcomas and characterized by activating mutations of the KIT and PDGFRA receptor tyrosine kinases. Following successful targeted therapy, the vast majority of patients eventually develop resistance and die of the disease. Genomic heterogeneity of secondary resistance mutations hampers the development of effective and long-lasting salvage therapies. Currently, no available drug (clinical or experimental) targets this broad spectrum of resistance.In the first funding period, we have on the one hand screened particularly for compounds inhibiting D816 mutations while on the other hand we rationally designed compounds with combined exon 17 and 13 activity. Most recently we have further modified these compounds into a first set of leads for covalent KIT-inhibitors, a yet unexploited strategy to target KIT. We have further developed a novel covalent allosteric inhibitor (CAI) of AKT displaying high potency in our GIST models as a complementing strategy to target oncogenic signaling. We underlined the ongoing success of this cooperation by five high impact publications and the patent application for said CAIs.Expanding our initial screening approach we have introduced a considerably larger compound library (n = 35,000) and refined our workflow now enabling us to dramatically increase throughput. We have broadened our armamentarium of GIST models for example by developing the first GIST-T1 subline harboring the critical KITV654A secondary mutation as well as the first TKI-resistant PDGFRAD842V cell line. For the second funding period, we plan to tackle the clinically dictated need for novel potent inhibitors of GIST oncogenic signaling by a threefold strategy. Thus, we will 1. Further refine and characterize our novel covalent KIT-inhibitors in vitro and in vivo. 2. Determine the efficacy and therapeutic window of our novel AKT-inhibitor (borussertib) in vivo. 3. Apply our new extensive compound library to identify specific inhibitors against KITV654A not blocking VEGFR as well as against PDGFRA G680R/D842V double and G652E/V658A/D842V triple mutant GIST. This funding period will enable us to realize the transition of a novel set of compounds into advanced preclinical development. Combining our resources and complementary expertise in drug development and disease-specific validation will thus enable us to discover specific inhibitors addressing the yet unmet medical needs of patients with a rare cancer.

• DFG Programme: Research Grants