Abstract 1141: CDK9 inhibition is selective for transcriptionally addicted tumors harboring MYC genomic amplifications

Abstract Transcriptional deregulation is a hallmark of many cancers, including a subset that are “transcriptionally addicted” and depend on high levels of transcription for oncogenic program genes. Although these tumors are thought to be highly susceptible to targeting of the transcriptional apparatus, their molecular definition remains challenging. To better define molecular sensitivity to transcriptional inhibition, we profiled pan-cancer sensitivity to KB-0742 — a potent, selective, and orally bioavailable small molecule inhibitor of the transcription elongation cofactor CDK9. Multiplexed sensitivity profiling across ~1, 000 adherent and suspension immortalized cell lines using the Broad PRISM platform revealed lineage and molecular determinants of sensitivity. Consistent with prior reports, MYC genomic amplification emerged as a key driver of CDK9 inhibitor sensitivity, and this was especially pronounced in non-small cell lung cancer. Sensitivity to CDK9 inhibition was further observed in MYC amplified/over-expressed ex vivo primary patient tumor cell cultures and patient-derived xenografts. Analysis of the temporal kinetics of CDK9 inhibition revealed a rapid collapse of oncogenic transcription programs comprised largely of short half-life transcripts including key oncogenes such as MYC and MCL1. In CDK9 sensitive ex vivo and in vivo models, suppression of oncogenic transcription for 8 hours was followed by apoptosis. In ex vivo models, CDK9 inhibitor sensitivity was observed for both treatment naïve and heavily pretreated patient samples. For in vivo models, CDK9 inhibition on an intermittent dosing schedule achieved sustained target coverage, as evidenced by both direct readouts of CDK9 activity and corresponding transcriptional response, and ultimately resulted in sustained tumor growth inhibition in multiple solid tumor types. These data suggest that MYC genomic amplification may serve as an important feature defining sensitivity to CDK9 inhibition in patients with advanced solid tumors. Citation Format: Melinda A. Day, Nikolaus D. Obholzer, Akanksha Pandey, Tom Chen, Tong Liang, Rosa A. Villagomez, Mulini Pingili, Jost V. Koren, David B. Freeman, Holly M. Nguyen, Jennifer L. Conor, Eva Corey, Matthew G. Reese, Andrew Boghossian, Brienne Engel, Melissa M. Ronan, Jennifer A. Roth, Joesph P. Vacca, Peter B. Rahl, Marius S. Pop, Benjamin W. Trotter, Charles Y. Lin, Jorge C. DiMartino, Pavan Kumar, Douglas C. Saffran. CDK9 inhibition is selective for transcriptionally addicted tumors harboring MYC genomic amplifications abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81 (13Suppl): Abstract nr 1141.