APC Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer

• Published in: Molecular cancer therapeutics Vol. 16; no. 4; pp. 752 - 762
• Main Authors: Tanaka, Noritaka, Mashima, Tetsuo, Mizutani, Anna, Sato, Ayana, Aoyama, Aki, Gong, Bo, Yoshida, Haruka, Muramatsu, Yukiko, Nakata, Kento, Matsuura, Masaaki, Katayama, Ryohei, Nagayama, Satoshi, Fujita, Naoya, Sugimoto, Yoshikazu, Seimiya, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.04.2017
• Subjects: Adenomatous polyposis coli; Adenomatous polyposis coli protein; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Binding Sites; Biomarkers; Biomarkers, Tumor - genetics; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Drug resistance; Enzyme Inhibitors - pharmacology; Gene expression; HCT116 Cells; Heterocyclic Compounds, 3-Ring - pharmacology; HT29 Cells; Humans; Imides - pharmacology; Inhibitors; LEF protein; Mutants; Mutation; Polyposis coli; Protein Binding; Quinolines - pharmacology; Sensitivity; Signaling; Sulfones - pharmacology; Tankyrases - antagonists & inhibitors; Transcription; Triazoles - pharmacology; Tumor cell lines; Tumorigenesis; Wnt protein; Wnt Signaling Pathway - drug effects; β-catenin
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-16-0578

In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in the ( ) 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 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 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 mutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics. .