In most
colorectal cancers, Wnt/β-
catenin signaling is activated by loss-of-function mutations in the
adenomatous polyposis coli (APC) gene and plays a critical role in
tumorigenesis.
Tankyrases poly(
ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-
catenin, and upregulate β-
catenin signaling.
Tankyrase inhibitors downregulate β-
catenin and are expected to be promising
therapeutics for
colorectal cancer. However,
colorectal cancer cells are not always sensitive to
tankyrase inhibitors, and predictive
biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-form APC mutations predict the sensitivity of
colorectal cancer cells to
tankyrase inhibitors. By using well-established
colorectal cancer cell lines, we found that
tankyrase inhibitors downregulated β-
catenin in the drug-sensitive, but not resistant,
colorectal cancer cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed "short" truncated APCs lacking all seven β-
catenin-binding 20-amino
acid repeats (20-AARs). In contrast, the drug-resistant cells possessed "long" APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased β-
catenin, Tcf/LEF transcriptional activity and its target gene AXIN2 expression. Under these conditions,
tankyrase inhibitors were able to downregulate β-
catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants, whereas they exert a dominant-negative effect on Axin-dependent β-
catenin degradation caused by
tankyrase inhibitors. Finally, we established 16 patient-derived
colorectal cancer cells and confirmed that the
tankyrase inhibitor-responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of APC mutations, the most common genetic alteration in
colorectal cancers, for molecular targeted
therapeutics. Mol
Cancer Ther; 16(4); 752-62. ©2017 AACR.