Regulation of oncogenic transcription and tumor growth in pediatric cancers by the CDK9 inhibitor KB-0742

Background: Disruption of transcriptional regulatory networks that drive normal cellular differentiation and development can result in oncogenic transformation addiction. Many pediatric sarcomas are defined by/harbor fusion proteins, resulting from chromosomal translocations such as the EWSR1 gene fused to an ETS family transcription factor (TF) (FLI1 or ERG) Ewing sarcoma (ES), PAX3/PAX7 FOXO1 alveolar rhabdomyosarcoma (ARMS). In neuroblastoma, MYCN, a member MYC TFs, is often amplified localizes super enhancer regions, where it rewires lineage-specific programs driving oncogenesis. Oncogenic TFs have proven difficult target directly; we others proposed targeting associated co-regulators inhibit their activity. CDK9 interacts with many essential for TF-mediated elongation through phosphorylation C-terminal domain RNA pol II. KB-0742 potent, selective, orally bioavailable inhibitor currently clinical shows antitumor activity preclinical models neuroblastoma. Materials Methods: Cell lines low passage patient-derived cells (PDCs) were tested antiproliferative effects KB-0742, using either Titer Glo (Promega) Alamar Blue cell viability reagent (Bio-Rad). Pharmacodynamic (PD) markers treatment, including phospho-SER2 (pSER2) on II, MYC, cleaved poly ADP ribose polymerase (PARP), measured by Western blot. The was evaluated xenograft (PDX) ES ARMS vivo. Tumor samples plasma collected determine PD drug concentrations, respectively. transgenic TH-MYCN model neuroblastoma used study KB-0742. All vivo performed according IACUC guidelines. Results: decreased immortalized PDCs ES, ARMS, MYCN amplification more sensitive treatment. KB-0742–treated had pSER2, loss expression induction PARP. treatment mouse resulted regression established tumors. PDX inhibited tumor growth. Analysis revealed decreases pSER2 function TFs. Conclusions: inhibits growth multiple types modulating key being phase I dose-escalation trial patients relapsed refractory solid tumors NHL (NCT04718675). Conflict interest: Ownership: CN, CYL, DCS, PK, SN-AA report stock ownership Kronos Bio, Inc. JD reports Inc., Bristol-Myers Squibb Company. JN Certis Oncology Solutions. TH NanoString Technologies. Advisory Board: FDC uncompensated consultancy Shasqi, Y-mAbs Therapeutics, Biosplice Daiichi Sankyo Co., Ltd., Sanofi-Aventis U.S., LLC. Corporate-sponsored Research: JD, SN-AA, employment at Other Substantive Relationships: institutional research support Eisai Ltd.