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Translational Therapeutics

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

British Journal of Cancer volume 130, pages 151–162 (2024)Cite this article

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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.

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Fig. 1: Colorectal cancer (CRC) patient-derived cells (PDCs) with ‘short’ APC mutations are sensitive to tankyrase inhibitors.
Fig. 2: Active β-catenin level marks tankyrase inhibitor-sensitive cells in the CRC PDCs with ‘long’ APC mutations.
Fig. 3: Tankyrase inhibitor sensitivity in the CRC PDCs correlates with β-catenin activation status in the original tumor tissues.
Fig. 4: Frequency of oncogenic driver mutations in the tankyrase inhibitor–responsive and –resistant CRC PDCs with APC mutations.
Fig. 5: Sensitivity of APC-wild CRC PDCs to tankyrase inhibitors and related molecular pathways.

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Data availability

The gene expression data have been deposited in the Gene Expression Omnibus (accession numbers: GSE217758, GSE232209). Other data generated or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Noritaka Tanaka, Yuki Shimizu, Bo Gong, Yuki Takahashi, Tomoko Oh-hara, Motoyoshi Iwakoshi, Shuhei Ishii, and Yuting Zhou for technical and experimental support and members of Seimiya laboratory for invaluable discussion. We thank Gabrielle White Wolf, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science [Scientific Research (B) 19H03523 and622H02931 to Hiroyuki Seimiya and Scientific Research (C) 18K07337 to Tetsuo Mashima], Project for Cancer Research and Therapeutic Evolution (167708578 to H. Seimiya), Practical Research for Innovative Cancer Control (19090105 and 22580621 to H. Seimiya), Project for Promotion of Cancer Research and Therapeutic Evolution (23810633 to T. Mashima), Japan Agency for Medical Research and Development, and grants from Nippon Foundation (to H. Seimiya) and Takeda Science Foundation (to H. Seimiya).

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Author notes

  1. These authors contributed equally: Mingjue Chen, Tetsuo Mashima, Taichi Oishi.

Authors and Affiliations

  1. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan

    Mingjue Chen, Tetsuo Mashima, Taichi Oishi, Yukiko Muramatsu, Naomi Kawata, Shun Morino, Ayane Nakamura, Saori Inaba, Xunmei Yuan, Ayana Sato, Haruka Yoshida, Myung-Kyu Jang, Anna Mizutani & Hiroyuki Seimiya

  2. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    Mingjue Chen, Taichi Oishi, Shun Morino, Kohei Maruyama, Mai Suzuki, Ayana Sato, Myung-Kyu Jang, Ryohei Katayama & Hiroyuki Seimiya

  3. Division of Experimental Chemotherapy, Cancer Chemotherapy Center, JFCR, Tokyo, Japan

    Yosuke Seto, Kohei Maruyama, Mai Suzuki & Ryohei Katayama

  4. Division of Pathology, The Cancer Institute, JFCR, Tokyo, Japan

    Manabu Takamatsu & Kengo Takeuchi

  5. Gastroenterological Chemotherapy, Cancer Institute Hospital, JFCR, Tokyo, Japan

    Naomi Kawata & Kensei Yamaguchi

  6. Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan

    Ayane Nakamura & Hiroyuki Seimiya

  7. Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Saitama, Japan

    Fumiyuki Shirai

  8. Gastroenterological Surgery, Cancer Institute Hospital, JFCR, Tokyo, Japan

    Satoshi Nagayama

  9. Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, Japan

    Satoshi Nagayama

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Contributions

MC, TM, TO: conceptualization, methodology, validation, formal analysis, investigation; writing original draft, review & editing, visualization. YM: methodology, validation, investigation, resources, writing original draft, review & editing, visualization. YS: software, investigation, resources, data curation, writing original draft. MT: validation, formal analysis, investigation, resources, writing original draft. NK, AN, SI, XY, M-KJ, AM: methodology, investigation. SM: methodology, validation, formal analysis, investigation, review & editing, visualization. KM: investigation, resources. MS: investigation, resources. AS: validation, investigation, visualization. HY: methodology, validation, investigation; visualization. KT: resources. KY: conceptualization, resources, review & editing. FS, SN: resources, review & editing. RK: conceptualization, investigation, resources, data curation, review & editing. HS: conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, writing original draft, review & editing, visualization, supervision, project administration, funding acquisition. All the authors drafted or revised the manuscript, approved the final version, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Hiroyuki Seimiya.

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Competing interests

HS received research grants from the Nippon Foundation and Takeda Science Foundation and holds a patent of RK-582 and related chemical compounds. FS holds a patent of RK-582 and related chemical compounds. RK received a research grant from TOPPAN. The other authors declare no competing interests.

Ethics approval and consent to participate

This study was performed in accordance with the Declaration of Helsinki under approval from the Institutional Review Board of Japanese Foundation for Cancer Research (JFCR) (Tokyo, Japan) and the written informed consent of patients. Animal procedures were carried out, following national laws and policies (Guidelines for Proper Conduct of Animal Experiments, Science Council of Japan, 2006) in the animal experiment room at JFCR according to protocols approved by the JFCR Animal Care and Use Committee.

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Chen, M., Mashima, T., Oishi, T. et al. APC/PIK3CA mutations and β-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells. Br J Cancer 130, 151–162 (2024). https://doi.org/10.1038/s41416-023-02484-8

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