RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model

Aberrant activation of the Wnt/β-catenin signaling pathway plays a crucial role in driving tumorigenesis and promoting the proliferation of colorectal cancer cells. While porcupine inhibitors have been explored as a therapeutic option by blocking the secretion of Wnt ligands, their clinical impact may be limited in colorectal cancer because the majority of these tumors arise from loss-of-function mutations in the adenomatous polyposis coli (APC) gene, which operates downstream of Wnt ligands. This loss of APC function disrupts normal regulatory mechanisms, leading to unchecked activation of β-catenin and subsequent tumor growth.

Tankyrase enzymes contribute to this process by poly(ADP-ribosyl)ating (PARylating) Axin, a key negative regulator of β-catenin. This post-translational modification marks Axin for ubiquitin-dependent degradation, thereby facilitating the accumulation of β-catenin within the cell. Consequently, tankyrase inhibitors have emerged as a promising strategy to downregulate β-catenin and suppress the growth of colorectal cancer cells that harbor APC mutations. By preventing the degradation of Axin, these inhibitors restore a critical control mechanism within the Wnt/β-catenin pathway.

In this context, we report the development of a novel tankyrase-specific inhibitor, RK-287107, which demonstrates significantly greater potency than the previously reported inhibitor G007-LK. RK-287107 inhibits tankyrase-1 and tankyrase-2 four- and eight-fold more potently, respectively. In colorectal cancer cells with truncated APC mutations, RK-287107 treatment leads to the accumulation of Axin2 and the subsequent downregulation of β-catenin. This effect is accompanied by a reduction in T-cell factor/lymphoid enhancer factor reporter activity and the decreased expression of downstream target genes, which are critical for tumor growth.

Consistent with its molecular effects, RK-287107 was found to inhibit the growth of APC-mutated, β-catenin-dependent colorectal cancer cell lines, such as COLO-320DM and SW403, while having no significant impact on APC-wild, β-catenin-independent cells like RKO. Moreover, both intraperitoneal and oral administration of RK-287107 in NOD-SCID mice bearing COLO-320DM tumors resulted in marked tumor growth suppression. The degree of tumor inhibition observed correlated well with pharmacodynamic biomarkers, notably the accumulation of Axin2 and the downregulation of MYC, underscoring the compound’s effectiveness in modulating the Wnt/β-catenin pathway.

These findings provide compelling proof-of-concept evidence that RK-287107 exerts a potent antitumor effect in APC-mutated colorectal cancer models. By specifically targeting tankyrase activity, this novel inhibitor holds significant potential for development as a molecular therapy aimed at correcting the dysregulated Wnt/β-catenin signaling that is central to the pathogenesis of colorectal cancer. Further studies will be essential to explore its clinical applicability and to determine whether this approach can be extended to other tumor types driven by similar molecular mechanisms.