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Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.

Gastrointestinal stromal tumor (GIST) is the most common GI sarcoma and frequently harbor oncogenic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinases. While type II tyrosine kinase inhibitors (TKIs) revolutionized the treatment of KIT-mutant GIST, they are thought to be ineffective for many PDGFRA-mutant GIST cases. Over 80% of PDGFRA mutations in GIST occur in exon 18 and patients with the most common mutation, D842V, are resistant to imatinib and other type II TKIs, leading to poor outcomes. However, beyond D842V, numerous other PDGFRA exon 18 mutations have been observed. From curated data of a large cohort of PDGFRA-mutant GISTs, we have identified nearly 50 unique PDGFRA exon 18 mutations, including both point mutations and complex indels. Although it is largely unknown how these mutations respond to imatinib, currently most, if not all, PDGFRA exon 18 mutations are assumed to be imatinib resistant. Using cell models, we tested some of the most commonly observed mutations in this cohort. Contrary to dogma, we observed that some exon 18 mutations tested were imatinib sensitive. We also observed that imatinib sensitivity seemed to be dependent on the properties of the residue in the 842-codon position, which encodes a key auto-inhibitory residue. We then hypothesized that imatinib sensitivity of every known or future reported PDGFRA exon 18 mutation might be predicted based on the 842 residue. To test the predictive potential of the 842 residue, we created mutagenic libraries that included every amino acid substitution at the 842 position. We expressed each mutation in Ba/F3 cells and assessed imatinib sensitivity via immunoblotting for phosphorylated-PDGFRA. Overall, 40% of tested mutations were sensitive to imatinib, further debunking the belief that all PDGFRA exon 18 mutations are imatinib resistant. In agreement with our hypothesis, we found that any hydrophobic residue at the 842 position conferred imatinib resistance (IC50 > 100nM), and all other amino acids tested to date were imatinib sensitive (IC50 < 100nM). Based on these data alone, over 55% of the 50 unique mutations identified from our PDGFRA-mutant GIST patient cohort would be predicted to be imatinib sensitive, demonstrating the importance of understanding the biochemical properties of various exon 18 mutations to predict treatment outcomes. Our predictive model would help identify patients with PDGFRA exon 18 mutations that could benefit from using front-line imatinib as an alternative to avapritinib, which has been recently approved for first-line treatment for all PDGFRA exon 18 mutant GIST. Imatinib, which has been used clinically for over 20 years, has a superior safety and tolerability profile compared to avapritinib. This paradigm shifting approach has the potential to transform patient care and outcomes by optimizing the sequencing of TKIs for PDGFRA-mutant GIST patients. Citation Format: Homma M. Khosroyani, Lillian R. Klug, Johanna Falkenhorst, Sebastian Bauer, Michael C. Heinrich. Predicting imatinib responses in exon 18 PDGFRA-mutant GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 660.

© 2017 Elsevier Inc. The bacterial flagellar motor drives the rotation of helical flagellar filaments to propel bacteria through viscous media. It consists of a dynamic population of mechanosensitive stators that are embedded in the inner membrane and activate in response to external load. This entails assembly around the rotor, anchoring to the peptidoglycan layer to counteract torque from the rotor and opening of a cation channel to facilitate an influx of cations, which is converted into mechanical rotation. Stator complexes are comprised of four copies of an integral membrane A subunit and two copies of a B subunit. Each B subunit includes a C-terminal OmpA-like peptidoglycan-binding (PGB) domain. This is thought to be linked to a single N-terminal transmembrane helix by a long unstructured peptide, which allows the PGB domain to bind to the peptidoglycan layer during stator anchoring. The high-resolution crystal structures of flagellar motor PGB domains from Salmonella enterica (MotBC2) and Vibrio alginolyticus (PomBC5) have previously been elucidated. Here, we use small-angle X-ray scattering (SAXS). We show that unlike MotBC2, the dimeric conformation of the PomBC5 in solution differs to its crystal structure, and explore the functional relevance by characterising gain-of-function mutants as well as wild-type constructs of various lengths. These provide new insight into the conformational diversity of flagellar motor PGB domains and experimental verification of their overall topology.