E-MTAB-2446 - Effect of Tankyrase inhibitior NVP-TNKS656 on Wnt/β-catenin pathway in the treatment of colorectal cancer
Released on 10 August 2015, last updated on 27 October 2015
Strong activation of the oncogenic Wnt/beta-catenin pathway is a main mechanism of resistance to FOXO3a-induced apoptosis promoted by PI3K and AKT inhibitors in colorectal cancer (CRC). Reducing Wnt/beta-catenin activity would sensitize colorectal tumors to these inhibitors. However, no Wnt/beta-catenin signaling inhibitor has proven clinical potential yet. Recently, inhibitors that block tankyrases were shown to reduce colon cancer cell proliferation by decreasing nuclear beta-catenin. We aim to identify determinants of response to these novel Wnt-inhibitors. Therefore, we treated in vivo three different patient-derived xenograft models (PDX; P2, P5 and P30) growing subcutaneously in NOD SCID mice with the novel tankyrase inhibitor NVP-TNKS656.
transcription profiling by array, compound treatment design, in vivo
Tankyrase inhibition blocks Wnt/β-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Oriol Arqués, Irene Chicote, Isabel Puig, Stephan P. Tenbaum, Guillem Argilés, Rodrigo Dienstmann, Natalia Fernández, Ginevra Caratù, Judit Matito, Daniel Silberschmidt, Jordi Rodon, Stefania Landolfi, Aleix Prat, Eloy Espín, Ramón Charco, Paolo Nuciforo, Ana Vivancos, Wenlin Shao, Josep Tabernero, Héctor G. Palmer. , PMID:26224873