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Genetics and Genomics

Significance of homologous recombinant deficiency as a biomarker for drug sensitivity in colorectal cancer

British Journal of Cancer volume 132, pages 533–542 (2025)Cite this article

Subjects

Abstract

Background

Colorectal cancer (CRC) is a substantial global health concern due to its limited treatment options, especially for oxaliplatin (L-OHP) regimen resistance. This study used organoid-based screening methodologies to evaluate drug responses in CRC while validating the approach with patient-derived CRC organoids and investigating potential biomarkers.

Methods

Patient-derived organoids were created from CRC surgical specimens, and drug screening were performed. Selected organoids with high and low L-OHP sensitivity underwent next-generation sequencing (NGS), and in vivo experiments using xenotransplantation were used to validate in vitro results. Moreover, the clinical application of homologous recombination deficiency (HRD) as a biomarker was investigated.

Results

Organoid drug screening revealed differences in L-OHP sensitivity among 34 patient-derived CRC organoids, and NGS deemed HRD as a potential biomarker. In vivo experiments validated the correlation between HRD status and L-OHP sensitivity, and clinical data suggested the potential of HRD as a biomarker for recurrence-free survival in patients treated with L-OHP. Additionally, HRD exhibited potential as a biomarker for other platinum agents and poly (ADP-ribose) polymerase inhibitors in CRC.

Conclusions

The study underscores HRD as a potential biomarker for predicting L-OHP sensitivity, expanding its application to other drugs in CRC. Organoid screening is reliable, providing insights into the intricate association between genetic features and treatment responses.

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Fig. 1: The overview of the organoid-based drug screening.
Fig. 2: L-OHP sensitivity correlated with HRD status.
Fig. 3: Successful upregulation of homologous recombination repair genes inhibits L-OHP-induced DNA damage.
Fig. 4: HRD-low organoid-derived tumours were resistant to L-OHP treatment in vivo.
Fig. 5: Kaplan–Meier curves for postoperative recurrence-free survival in patients with stage II/III colorectal cancer who underwent adjuvant chemotherapy.
Fig. 6: HRD status predicts sensitivity to other platinum agents and PARP inhibitors but not for anti-EGFR agents.

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Data availability

Data used for the manuscript will be available from the corresponding author upon reasonable request.

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Funding

This work was supported by JST SPRING (Grant Number JPMJSP2123) and Sysmex Corporation (Hyogo, Japan).

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Authors and Affiliations

  1. Department of Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Yujin Kato, Ryo Seishima, Kaoru Hattori, Hirochika Kato, Hiroki Ishida, Kohei Shigeta, Koji Okabayashi & Yuko Kitagawa

  2. Department of Surgery, Fujita Health University, Toyoake, 470-1192, Japan

    Ryo Seishima

  3. Division of Gene Regulation, Oncology Innovation Center, Fujita Health University, Toyoake, 470-1192, Japan

    Eiji Sugihara, Tetsuya Takimoto & Hideyuki Saya

  4. Research Promotion Headquarters, Open Facility Center, Fujita Health University, Toyoake, 470-1192, Japan

    Eiji Sugihara

  5. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Kohei Nakamura & Hiroshi Nishihara

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  1. Yujin Kato
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Contributions

Yujin K, RS, KH and HI carried out experiments. Yujin K, HK and KN collected the samples. Yujin K, ES, KS, KO, TT, HN, HS and Yuko K analysed the data. Yujin K and RS conceived experiments and wrote the paper. All authors had final approval of the submitted and published versions.

Corresponding author

Correspondence to Ryo Seishima.

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Competing interests

Yuko K received grants from TAIHO PHARMACEUTICAL CO., LTD.; CHUGAI PHARMACEUTICAL CO., LTD.; Yakult Honsha Co. Ltd.; DAIICHI SANKYO COMPANY; Merck Serono Co., Ltd; AsahiKASEI Co., Ltd; EA Pharma Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Factory Inc.; SHIONOGI & CO., LTD.; KAKEN PHARMACEUTICAL CO., LTD.; Kowa Pharmaceutical Co., Ltd.; Astellas Pharma Inc.; MEDICON INC., Dainippon Sumitomo Pharma Co., Ltd.; Taisho Toyama Pharmaceutical Co., Ltd.; Kyouwa Hakkou Kirin Co., Ltd.; Pfizer Japan Inc.; ONO PHARMACEUTICAL CO., LTD.; NIHON PHARMACEUTICAL CO., LTD.; Japan Blood Products Organization; Medtronic Japan Co., Ltd.; Sanofi K.K.; Eisai Co., Ltd; TSUMURA & CO.; KCI Licensing, Inc.; ABBOTT JAPAN CO., LTD; and FUJIFILM Toyama Chemical Co., Ltd., outside the submitted work.

Ethics approval and consent to participate

The protocol of this study was approved by The Ethics Committee of Keio University, and all methods were performed in accordance with the Helsinki Declaration of 1996 (approval number: 20150148). The Ethics Committee at the Laboratory Animal Care and Use Committee at Keio University School of Medicine approved all experimental procedures, and the study was performed in accordance with the Care and Use of Laboratory Animals (NIH). Informed consent was obtained from all individual participants included in the study.

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Kato, Y., Seishima, R., Hattori, K. et al. Significance of homologous recombinant deficiency as a biomarker for drug sensitivity in colorectal cancer. Br J Cancer 132, 533–542 (2025). https://doi.org/10.1038/s41416-025-02950-5

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