Tankyrase inhibition in Metastatic Melanoma Immunotherapy

Waaler lab, Department of Immunology, Oslo University Hospital

The Cell Signaling and Drug Discovery research group is located at the Department of Immunology (IMM) at Oslo University Hospital – Rikshospitalet and is led by Group Leader Jo Waaler www.ous-research.no/waaler. The group will consist of 2-3 postdocs and 2-3 technicians along with Master's students. The research group is also associated with the RCN Centre of Excellence (SFF) - Hybrid Technology Hub - Centre for Organ on a Chip-Technology: www.med.uio.no/hth/english. Jo Waaler has functioned as a supervisor for 11 Master’s students.

Background

The research group focuses on tankyrase 1 and tankyrase 2 (TNKS1/2), enzymes from the PARP family that regulate protein activity, interactions, and degradation through mono- or poly-ADP-ribosylation and downstream cell signaling. TNKS1/2 proteins are key players in the regulation of WNT/β-catenin and Hippo signaling pathways, which are implicated in various diseases, including cancer, immune evasion and fibrosis. Consequently, significant efforts have been dedicated to developing selective TNKS1/2 inhibitors.

Oslo University Hospital has established itself as a leading center for chemical biology and has developed a small-molecule TNKS inhibitor program. These inhibitors modulate several target proteins, such as AXIN1 and AXIN2 in the β-catenin destruction complex, thereby inhibiting WNT/β-catenin signaling, and AMOT proteins in the Hippo signaling pathway, leading to YAP signaling inhibition.

40-65% of melanoma patients do not respond to immune checkpoint inhibitor (ICPi) therapy. Resistance mechanisms are currently being mapped, and cellular signaling pathways, such as YAP and WNT/β-catenin signaling, emerge as promising targets for therapeutical intervention. β-catenin is the key transcriptional regulator of WNT/β-catenin signaling, and β-catenin-induced immune evasion is found in