Diffuse large B‐cell lymphoma cell‐cycle progression requires the cyclin‐G associated kinase (GAK), a novel drug target from machine learning‐enabled phenotypic screening

Background: Recurrent genomic alterations in specific cancers reveal tumor drivers that inform the development of therapeutic approaches. In diffuse large B-cell lymphoma (DLBCL), oncoprotein-focused drug has achieved limited success. Phenotypic screening is an emerging alternative can be leveraged through machine-learning analysis. Under this paradigm, we strong potential DLBCL inhibiting cyclin-G associated kinase (GAK). GAK participates clathrin-mediated endocytosis and regulates mitotic-spindle alignment. been minimally explored cancer therapeutics a novel target DLBCL. Methods: We performed first-of-its-kind screen inhibitors followed by machine learning-based analysis using our in-house identification platform, idTRAX. analyzed gene-expression data for 414 previously untreated patients (Lenz cohort). Immunofluorescent microscopy was to visualize mitotic effect inhibition. Results: Our revealed as both activated (ABC) germinal center (GCB) derived cell lines with complete sparing peripheral-blood mononuclear cells. Analysis found tumors high expression had dramatically worse overall survival compared those low (p = 0.0002). inhibition results profound disruption progression mitosis, potently triggering spindle assembly checkpoint causing accumulation G2 before onset apoptosis. Additionally, showed correlation between RB1, encoding suppressive master cell-cycle regulator retinoblastoma-associated protein (RB, p < 0.0001). The RIVA U2932 completely lack RB show sensitivity response Pooled analyses increased ABC-derived (mean EC50 0.2817 µM) GCB 0.6517 µM, 0.0078). spindles shattering chromosomes these Multiple participant molecules are implicated candidate substrates under investigation define key mechanisms. Conclusion: GAK’s role alignment represents critical dependency tumors, particular deregulation due loss function. synthesis synergistic targets may new strategies translation clinical trials unmet needs. research funded by: Florida Department Health Bankhead-Coley Cancer Research Program Keywords: Aggressive non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts interests pertinent abstract. V. Lemmon Employment or leadership position: Truvitech LLC H. A. Ali J. Schatz Consultant advisory role: WCG - ACI Clinical