Wnt/β-catenin signaling is activated in over 90% of human colorectal cancer. In particular, loss-of-function mutations of the tumor suppressor adenomatous polyposis coli (APC), a key negative regulator of Wnt/β-catenin signaling, occur in 90% of patients. The secreted Frizzled-related proteins (sFRPs) and Wnt inhibitory protein (WIF) regulate Wnt/b-catenin signaling. Both of proteins can bind Wnts, thereby inhibiting interactions between Wnt and Wnt receptors. Aberrant activation of Wnt/β-catenin signaling causes tumorigenesis and promotes the proliferation of colorectal cancer cells. Tankyrases (tankyrase-1 and tankyrase-2) are members of the poly(ADP-ribose) polymerase (PARP) family proteins. Tankyrase inhibitors downregulate β-catenin and suppress the growth of adenomatous polyposis coli (APC)-mutated colorectal cancer cells.

Herein, Anna Mizutani, et al reported a novel tankyrase-specific inhibitor RK-287107, which inhibits tankyrase-1 and tankyrase-2. In the present study, Anna Mizutani, et al showed that RK-287107 potently inhibits tankyrases but not PARP1 enzyme activity. RK-287107 causes Axin2 accumulation and downregulates β-catenin, T-cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated APC mutations. Consistently, RK-287107 inhibits the growth of APC-mutated (β-catenin-dependent) colorectal cancer cells but not the APC-wild (β-catenin-independent) colorectal cancer cells. Besides, orally given RK-287107 at tolerable doses suppresses tumor growth in a mouse xenograft model. Through blockade of the β-catenin signaling pathway, RK-287107 suppresses tumor growth of human colorectal cancer cells in mouse xenograft models.

All in all, RK-287107 exerts antitumor effect, and thus may have potential for tankyrase-directed molecular cancer therapy.