APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer

Noritaka Tanaka, Tetsuo Mashima, Anna Mizutani, Ayana Sato, Aki Aoyama, Bo Gong, Haruka Yoshida, Yukiko Muramatsu, Kento Nakata, Masaaki Matsuura, Ryohei Katayama, Satoshi Nagayama, Naoya Fujita, Yoshikazu Sugimoto, Hiroyuki Seimiya

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

In most colorectal cancers, Wnt/b-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 b-catenin, and upregulate b-catenin signaling. Tankyrase inhibitors downregulate b-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 b-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 b-catenin-binding 20-amino acid repeats (20-AARs). In contrast, the drug-resistant cells possessed "long"APCretaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased b-catenin, Tcf/LEF transcriptional activity and its target gene AXIN2 expression. Under these conditions, tankyrase inhibitors were able to downregulate b-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 b-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.

Original languageEnglish
Pages (from-to)752-762
Number of pages11
JournalMolecular Cancer Therapeutics
Volume16
Issue number4
DOIs
Publication statusPublished - 2017 Apr 1

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Tankyrases
Catenins
Adenomatous Polyposis Coli
Colorectal Neoplasms
Biomarkers
Mutation
Down-Regulation
Amino Acids
Pharmaceutical Preparations
APC Genes
Adenosine Diphosphate
Carcinogenesis
Up-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer. / 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.

In: Molecular Cancer Therapeutics, Vol. 16, No. 4, 01.04.2017, p. 752-762.

Research output: Contribution to journalArticle

Tanaka, N, Mashima, T, Mizutani, A, Sato, A, Aoyama, A, Gong, B, Yoshida, H, Muramatsu, Y, Nakata, K, Matsuura, M, Katayama, R, Nagayama, S, Fujita, N, Sugimoto, Y & Seimiya, H 2017, 'APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer', Molecular Cancer Therapeutics, vol. 16, no. 4, pp. 752-762. https://doi.org/10.1158/1535-7163.MCT-16-0578
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. / APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 4. pp. 752-762.
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AU - Tanaka, Noritaka

AU - Mashima, Tetsuo

AU - Mizutani, Anna

AU - Sato, Ayana

AU - Aoyama, Aki

AU - Gong, Bo

AU - Yoshida, Haruka

AU - Muramatsu, Yukiko

AU - Nakata, Kento

AU - Matsuura, Masaaki

AU - Katayama, Ryohei

AU - Nagayama, Satoshi

AU - Fujita, Naoya

AU - Sugimoto, Yoshikazu

AU - Seimiya, Hiroyuki

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