APCMutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer.
In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in theadenomatous 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-formAPCmutations 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 geneAXIN2expression. 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 ofAPCmutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics.Mol Cancer Ther; 16(4); 752-62. ©2017 AACR.
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.|Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
Noritaka
N
Tanaka
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Tetsuo
T
Mashima
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Anna
A
Mizutani
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.|Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Ayana
A
Sato
Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Aki
A
Aoyama
Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Bo
B
Gong
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Haruka
H
Yoshida
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Yukiko
Y
Muramatsu
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.|Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
Kento
K
Nakata
Graduate School of Public Health, Teikyo University, Tokyo, Japan.
Masaaki
M
Matsuura
Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Ryohei
R
Katayama
Department of Gastroenterological and Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
Satoshi
S
Nagayama
Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.|Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
Naoya
N
Fujita
Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
Yoshikazu
Y
Sugimoto
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. hseimiya@jfcr.or.jp.|Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
Hiroyuki
H
Seimiya
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007094:Imides / Q000494:pharmacology; D011485:Protein Binding; D011804:Quinolines / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C582305:G007-LK; D006575:Heterocyclic Compounds, 3-Ring; C585534:IWR-1 compound; D007094:Imides; D011804:Quinolines; D013450:Sulfones; D014230:Triazoles; C544261:XAV939; D038501:Tankyrases