Tankyrase Inhibition in Colorectal Cancer Therapeutics

Colorectal cancer is driven in the majority of cases by aberrant activation of the Wnt/β-catenin signalling pathway, most often through mutations in APC or β-catenin. Tankyrase enzymes (TNKS1 and TNKS2) catalyse poly(ADP-ribosyl)ation of the Axin proteins, marking them for degradation and thereby sustaining β-catenin–mediated transcription of proliferative and survival genes. Small-molecule inhibitors of tankyrase restore Axin levels, attenuate Wnt signalling and suppress tumour cell growth in preclinical models. Beyond single-agent activity, tankyrase inhibition has been shown to enhance the efficacy of established therapies, including chemotherapeutics and cell-cycle inhibitors. Translational studies in xenograft and organoid systems have validated the capacity of‐targeted TNKS inhibitors to reduce tumour burden and to delay the emergence of resistance. Key challenges to clinical application include on-target toxicity in intestinal epithelium, context-specific resistance mechanisms such as KRAS mutations, and the need for predictive biomarkers to guide patient selection. Continued refinement of inhibitor selectivity and delivery, as well as rational combination regimens, holds promise for integrating tankyrase inhibitors into future colorectal cancer treatment paradigms.

Research from Nature Portfolio

Recent studies describe MSC2504877, a drug-like small-molecule that selectively inhibits tankyrase activity in APC-mutant colorectal tumour cells. Genome-wide screens identified synergy between MSC2504877 and clinical CDK4/6 inhibitors, with combinations markedly enhancing G1 cell-cycle arrest and senescence compared with either agent alone. Mechanistically, dual treatment suppressed the compensatory upregulation of Cyclin D2 and Cyclin E2 and potentiated retinoblastoma protein dephosphorylation. In vivo, co-administration of MSC2504877 with a CDK4/6 inhibitor restrained the hyperproliferative phenotype of Apc-deficient intestinal stem cells. However, the presence of oncogenic KRAS mutations reversed the combination’s efficacy, highlighting a potential resistance route and underscoring the importance of molecular stratification in therapeutic design.

Tankyrase Inhibition in Colorectal Cancer Therapeutics publication trend

The graph below shows the total number of articles in tankyrase inhibition in colorectal cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Tankyrase: A member of the poly(ADP-ribose) polymerase family that modifies Axin proteins to regulate Wnt/β-catenin signalling.

Wnt/β-catenin signalling: A cascade controlling cell proliferation and differentiation, frequently dysregulated in colorectal cancer.

Axin: A scaffold protein in the β-catenin destruction complex whose stability determines Wnt pathway activity.

Poly(ADP-ribosyl)ation (PARylation): A post-translational protein modification catalysed by PARP enzymes, marking proteins for ubiquitin-mediated degradation.

CDK4/6 inhibitor: A small molecule that blocks cyclin-dependent kinases 4 and 6, preventing progression through the G1 phase of the cell cycle.

References

1. A New Wave of Targeting ‘Undruggable’ Wnt Signaling for Cancer Therapy: Challenges and Opportunities. Cells (2023).
2. Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding. British Journal of Pharmacology (2017).
3. A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors. Scientific Reports (2019).
4. The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance. Oncotarget (2016).
5. E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling. Oncotarget (2015).