Characterization And Therapeutic Harnessing Of Trail'S Pro-Tumorigenic And Pro-Apoptotic Functions In Cancer

Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is known for specifically killing many cancer cells. This has led to the clinical development of several agonists for TRAIL-Rs. However, while some cancer cells die in response to TRAIL, most primary cancer cells are resistant to TRAIL-based monotherapy. In resistant cells, TRAIL signaling can induce non-apoptotic, tumor-supporting effects. Hence, efficient therapy design requires understanding of the bivalent nature of TRAIL signaling. Here we demonstrate that, on the one hand, TRAIL–TRAIL-R signaling in cancer cells elicits the production of cytokines, most importantly CCL2, which promote the accumulation of alternatively activated, M2-like myeloid cells in the tumor microenvironment, consequently promoting tumor growth via a CCL2/CCR2 axis. On the other hand, we identified CDK9 inhibition as a powerful means to render many TRAIL-resistant cancer cells highly sensitive to TRAIL-induced apoptosis. Importantly, this combination was also highly effective in vivo and led to significant tumor regression in mouse models of lung cancer. Therefore, in certain cancer patients antagonizing endogenous TRAIL–TRAIL-R signaling may modulate the tumor microenvironment in favour of tumor regression, while in other cancer patients the combination of TRAIL-R agonists with CDK9 inhibitors should be considered as a highly active alternative therapy. Citation Format: Antonella Montinaro, Torsten Hartwig, Silvia von Karstedt, Itziar Areso Zubiaur, Johannes Lemke, Lucia Taraborelli, Silvia Surinova, Mona A. El-Bahrawy, Henning Walczak. Characterization and therapeutic harnessing of TRAIL’s pro-tumorigenic and pro-apoptotic functions in cancer [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 B18.