A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors

Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/ beta-cateninsignalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor of tankyrase MSC2504877 that inhibits the growth of APC mutant colorectal tumour cells. Parallel siRNA and drug sensitivity screens showed that the clinical CDK4/6 inhibitor palbociclib, causes enhanced sensitivity to MSC2504877. This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to palbocicliband MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors. The addition of MSC2504877 to palbociclibenhances G(1) cell cycle arrest and cellular senescencein tumour cells. MSC2504877 exposure suppresses the upregulation of Cyclin D2and Cyclin E2caused by palbocicliband enhances the suppression of phospho-Rb, providing a mechanistic explanation for these effects. The combination of MSC2504877 and palbociclibwas also effective in suppressing the cellular hyperproliferative phenotype seen in Apc defective intestinal stem cells in vivo. However, the presence of an oncogenic Kras p.G12D mutation in mice reversed the effects of the MSC2504877/ palbociclibcombination, suggesting one molecular route that could lead to drug resistance.