Abstract 5207: Organoid-based drug screening identifies CDK9 as a target for stratified treatment of high-grade serous ovarian cancer

Abstract High-grade serous ovarian cancer (HGSC) is the most common and lethal ovarian cancer type. Despite favorable response to first-line therapy, most HGSC patients eventually relapse. HGSC presents few recurrent mutations that could be used as therapeutic biomarkers and hence, the progress with genomic-based precision HGSC treatment has been limited. We therefore took a functional precision medicine approach and asked whether we could identify patient-specific vulnerabilities of refractory HGSC using patient-derived organoids. We have previously established a collection of HGSC organoids1, which is currently being expanded to a publicly accessible biobank of >100 stable and expandable cultures (OvaCure Collection, ovacurecollection.com). We also demonstrated that organoid drug responses correlate with clinical treatment outcomes1. Herein, in organoids from several HGSC patients, we performed a large-scale drug-response profiling of a library of 370 compounds. Of these, we found that inhibitors of CDK9 (CDK9i), but not other CDKs, demonstrated pronounced activity in subset of patients. CDK9i have not yet been thoroughly assessed for the treatment of HGSC, and only MYC overexpression has been considered as a sensitivity biomarker2. To explore the CDK9i responses in HGSC, we profiled 18 organoid cultures against selective CDK9i (AZD4573, VIP-152, NVP-2 and KB-0742). We observed a range of CDK9i-sensitivities in the patient cohort, from resistant cultures to exceptional responders. As all organoids have been previously characterized with whole genome- and RNA sequencing, we assessed genetic and transcriptomic differences between models to identify potential biomarkers of CDK9i sensitivity. MYC expression, biomarker of sensitivity in previous CDK9i clinical trials, did not correlate with CDK9i sensitivity in organoids (Pearson r = 0.244, p=0.346), suggesting its poor predictive value. However, we identified a set of genes, expression of which closely correlated with sensitivity (36 genes with Pearson r>0.7) or resistance (84 genes with Pearson r<-0.7) to CDK9i. For instance, expression of phosphodiesterase 3B (PDE3B) was correlated with CDK9i resistance (Pearson r = -0.744, p<0.001), while expression of ERBB3 was correlated with increased CDK9i sensitivity (Pearson r = 0.841, p<0.0001). Taken together, we demonstrate the application of an HGSC organoid biobank for identifying patient-specific targets, exceptional responder groups and potential CDK9i sensitivity biomarkers in HGSC. Results of this project could serve as a basis for designing a molecularly stratified CDK9 inhibitor-focused clinical trial in refractory HGSC patients. Citation Format: Wojciech Senkowski, David Fontaneda-Arenas, Yilin Li, Kari A. Lavikka, Aura Crispino, Jakub Červinka, Francesca Gorini, Kyriaki Driva, Laura Gall-Mas, Lidia Moyano-Galceran, Jaana Oikkonen, Yan-Jun Chen, Karolin Voßgröne, Elin Pietras, Jutta Huvila, Kaisa Huhtinen, Johanna Hynninen, Sampsa Hautaniemi, Krister Wennerberg. Organoid-based drug screening identifies CDK9 as a target for stratified treatment of high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5207.