Abstract B13: The impact of combined CDK9 inhibition and TRAIL treatment on NSCLC

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically kill cancer cells in vivo. On the basis of this, TRAIL-receptor (TRAIL-R) agonists were devised for clinical use. However, to date, TRAIL-R agonists have only shown limited therapeutic benefit in clinical trials. This can most likely be attributed to the fact that most primary human cancers are TRAIL resistant. It is therefore important to identify potent and cancer-selective TRAIL-sensitizers that overcome TRAIL resistance. Recently, the combination of CDK9 inhibition with TRAIL was found to effectively induce apoptosis in a panel of TRAIL-resistant non-small cell lung cancer (NSCLC) cell lines. Furthermore, tumors from NSCLC patients show high expression levels of CDK9, providing a rationale for targeting CDK9 in lung cancer. Here, we evaluate how effective the new TRAIL/CDK9 inhibition combination therapy is in treating lung cancer in an autochthonous mouse model (the KrasG12D/p53R172H) that closely recapitulates the human disease. We found that this combination was highly effective in vivo and led to a significant tumor regression and prolonged the survival of these mice. Our most recent results regarding these effects will be presented. Citation Format: Itziar Areso Zubiaur, Antonella Montinaro, Silvia von Karstedt, Johannes Lemke, Torsten Hartwig, Lucia Taraborelli, Silvia Surinova, Mona A. El-Bahrawy, Henning Walczak. The impact of combined CDK9 inhibition and TRAIL treatment on NSCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B13.