APC/PIK3CA mutations and β-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells

  • Br J Cancer. 2024 Jan;130(1):151-162. doi: 10.1038/s41416-023-02484-8.
Mingjue Chen  #  1  2 ,  Tetsuo Mashima  #  1 ,  Taichi Oishi  #  1  2 ,  Yukiko Muramatsu  1 ,  Yosuke Seto  3 ,  Manabu Takamatsu  4 ,  Naomi Kawata  1  5 ,  Shun Morino  1  2 ,  Ayane Nakamura  1  6 ,  Saori Inaba  1 ,  Xunmei Yuan  1 ,  Kohei Maruyama  2  3 ,  Mai Suzuki  2  3 ,  Ayana Sato  1  2 ,  Haruka Yoshida  1 ,  Myung-Kyu Jang  1  2 ,  Anna Mizutani  1 ,  Kengo Takeuchi  4 ,  Kensei Yamaguchi  5 ,  Fumiyuki Shirai  7 ,  Satoshi Nagayama  8  9 ,  Ryohei Katayama  2  3 ,  Hiroyuki Seimiya  10  11  12
Affiliations
  • 1. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.
  • 2. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
  • 3. Division of Experimental Chemotherapy, Cancer Chemotherapy Center, JFCR, Tokyo, Japan.
  • 4. Division of Pathology, The Cancer Institute, JFCR, Tokyo, Japan.
  • 5. Gastroenterological Chemotherapy, Cancer Institute Hospital, JFCR, Tokyo, Japan.
  • 6. Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
  • 7. Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Saitama, Japan.
  • 8. Gastroenterological Surgery, Cancer Institute Hospital, JFCR, Tokyo, Japan.
  • 9. Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, Japan.
  • 10. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan. [email protected].
  • 11. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. [email protected].
  • 12. Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan. [email protected].
  • # Contributed equally.
PMID: 37968472 DOI: 10.1038/s41416-023-02484-8
Abstract

Background: Aberrant Wnt/β-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, β-catenin repressors. Tankyrase inhibitors block Wnt/β-catenin signaling and colorectal Cancer (CRC) growth. We previously reported that 'short' APC mutations, lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs), are potential predictive biomarkers for CRC cell sensitivity to tankyrase inhibitors. Meanwhile, 'Long' APC mutations, which possess more than one 20-AAR, do not predict inhibitor-resistant cells. Thus, additional biomarkers are needed to precisely predict the inhibitor sensitivity.

Methods: Using 47 CRC patient-derived cells (PDCs), we examined correlations between the sensitivity to tankyrase inhibitors (G007-LK and RK-582), driver mutations, and the expressions of signaling factors. NOD.CB17-Prkdcscid/J and BALB/c-nu/nu xenograft mice were treated with RK-582.

Results: Short APC mutant CRC cells exhibited high/intermediate sensitivities to tankyrase inhibitors in vitro and in vivo. Active β-catenin levels correlated with inhibitor sensitivity in both short and long APC mutant PDCs. PIK3CA mutations, but not KRAS/BRAF mutations, were more frequent in inhibitor-resistant PDCs. Some wild-type APC PDCs showed inhibitor sensitivity in a β-catenin-independent manner.

Conclusions: APC/PIK3CA mutations and β-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-137849
    RK-582
    98.05%, Tankyrase Inhibitor
    target: PARP
    Research Areas: Cancer