Abstract 2565: CDK9 inhibitor KB-0742 is active in preclinical models of small-cell lung cancer

Abstract

Abstract Small-cell lung cancer (SCLC) is a highly aggressive malignancy, with a 5-year survival rate below 5%. In contrast to non-small cell lung cancer, in which treatment advancements have shown much success, there has not been significant progress in the development of new therapies for SCLC over the last 40 years. Thus, an urgent need exists to identify new and effective pharmacological interventions for these patients. Recent advancements in the understanding of the pathology of the disease has shown that SCLC tumorigenesis and evolution is governed by increased expression of neuroendocrine-associated and other proto-oncogenic transcription factors such as ASCL1, NEUROD1, and MYC. Thus, targeting transcription may be an effective therapeutic strategy. Cyclin-dependent kinase 9 (CDK9) is a serine-threonine kinase that is involved in transcriptional elongation through the phosphorylation of the RNA polymerase II. Additionally, CDK9 interacts with transcription factors such as MYC to promote activation of target genes. Inhibition of CDK9 results in disrupted transcriptional networks and inhibition of cancer cell proliferation and survival, making CDK9 an attractive target for the treatment of SCLC. We have developed a highly selective and orally bioavailable inhibitor of CDK9, KB-0742. Here we present the evaluation of KB-0742 activity in preclinical models of SCLC. Using the Broad PRISM platform, we evaluated the sensitivity of 24 SCLC cell lines. We observed a correlation between MYC copy number amplification and sensitivity with amplified lines having smaller AUC values than non-amplified lines (Mann-Whitney-Wilcoxon; P>0.05). We observed a similar trend of lower IC50 values with increasing levels of MYC expression in a separate cell-line screen that included 5 SCLC lines (Pearson’s correlation; P=0.71). We then evaluated KB-0742 activity in a panel of 6 patient-derived organoid (PDO) SCLC models with different treatment histories and compared to 4 standard-of-care (SOC) compounds. KB-0742 was more active than the SOC compounds, with maximum inhibition rates of over 90% for 5 of the 6 models. In a separate study of 4 treatment-naïve PDO models, KB-0742 was active in 3 different transcription factor-driven subtypes of SCLC, and the response correlated significantly with c-MYC and MYCL expression. Lastly, we used 4 patient-derived xenograft (PDX) models to evaluate KB-0742 activity in vivo. The tumor growth inhibition (TGI) rate ranged from 54% to 92%, with tumor regressions observed in 2 of the 4 models, and 1 model showed greater TGI with KB-0742 than the SOC. These data support the development of KB-0742 as a potential treatment for SCLC. Patients with relapsed or refractory solid tumors or non-Hodgkin lymphoma are currently being enrolled in a phase 1/2 clinical trial of KB-0742 (NCT04718675) with an expansion arm for SCLC being planned after the recommended phase 2 dose is identified. Citation Format: Melinda A. Day, Douglas C. Saffran, Tressa Hood, Nikolaus Obholzer, Akanksha Pandey, Charles Y. Lin, Pavan Kumar, Jorge DiMartino. CDK9 inhibitor KB-0742 is active in preclinical models of small-cell lung cancer [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 2565.