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GLI1 confers resistance to PARP inhibitors by activating the DNA damage repair pathway

Oncogene volume 43, pages 3037–3048 (2024)Cite this article

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A Correction to this article was published on 13 September 2024

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Abstract

Identifying the mechanisms of action of anticancer drugs is an important step in the development of new drugs. In this study, we established a comprehensive screening platform consisting of 68 oncogenes (MANO panel), encompassing 243 genetic variants, to identify predictive markers for drug efficacy. Validation was performed using drugs that targeted EGFR, BRAF, and MAP2K1, which confirmed the utility of this functional screening panel. Screening of a BRCA2-knockout DLD1 cell line (DLD1-KO) revealed that cells expressing SMO and GLI1 were resistant to olaparib. Gene set enrichment analysis identified genes associated with DNA damage repair that were enriched in cells overexpressing SMO and GLI1. The expression of genes associated with homologous recombination repair (HR), such as the FANC family and BRCA1/2, was significantly upregulated by GLI1 expression, which is indicative of PARP inhibitor resistance. Although not all representative genes of the nucleotide excision repair (NER) pathway were upregulated, NER activity was enhanced by GLI1. The GLI1 inhibitor was effective against DLD1-KO cells overexpressing GLI1 both in vitro and in vivo. Furthermore, the combination therapy of olaparib and GLI1 inhibitor exhibited a synergistic effect on DLD1-KO, suggesting the possible clinical application of GLI1 inhibitor targeting cancer with defective DNA damage repair. This platform enables the identification of biomarkers associated with drug sensitivity, and is a useful tool for drug development.

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Fig. 1: Summary of the transformation activity of 243 variants.
Fig. 2: Verification of the MANO panel.
Fig. 3: Identification of resistant variants to PARPi.
Fig. 4: Effect on DNA damage repair by the expression of SMO and GLI1 genes.
Fig. 5: Combination treatment of PARPi and GLI1 inhibitor in mouse xenograft model.

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The data generated in this study are available within the article and its supplementary table files.

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Acknowledgements

The authors thank the members of our division, particularly A. Maruyama-Shiino, Y. Ono, and M. Takeyama for technical assistance.

Funding

This study was supported by the grants of Practical Research for Innovative Cancer Control (grant no. JP22ck0106536), Program for Promoting Platform of Genomics based Drug Discovery (grant no. JP23kk0305018), and Moonshot Research and Development Program (grant no. JP22zf0127009) from Japan Agency for Medical Research and Development (AMED), and also supported by the JSPS Grants-in-Aid for Scientific Research (B) (grant no. JP21H02795).

Author information

Authors and Affiliations

  1. Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    Hiroshi Ikeuchi, Shinya Kojima, Toshihide Ueno, Masachika Ikegami, Rina Kitada, Hiroyuki Mano & Shinji Kohsaka

  2. Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan

    Hiroshi Ikeuchi, Kazuya Takamochi & Kenji Suzuki

  3. Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    Yusuke Matsuno, Rika Kusumoto-Matsuo & Ken-ichi Yoshioka

  4. Department of Musculoskeletal Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

    Masachika Ikegami

  5. Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

    Hitomi Sumiyoshi-Okuma, Yuki Kojima & Kan Yonemori

  6. Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

    Yasushi Yatabe

Authors
  1. Hiroshi Ikeuchi
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  2. Yusuke Matsuno
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  3. Rika Kusumoto-Matsuo
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  4. Shinya Kojima
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  8. Hitomi Sumiyoshi-Okuma
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  9. Yuki Kojima
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  12. Kazuya Takamochi
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  14. Ken-ichi Yoshioka
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  15. Hiroyuki Mano
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  16. Shinji Kohsaka
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Contributions

SK conceived of the project and designed the study. SK and HM developed the study methodology. HI, YM., and RKM performed experiments. HO, YK, KY, and YY provided clinical samples. HI, TU, MI, and SK analyzed and interpreted the data. KY, KT, KS, and HM provided the administrative and technical support. HI, YM, RKM, HM, and SK wrote and edited the manuscript with feedback from all authors.

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Correspondence to Shinji Kohsaka.

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Ikeuchi, H., Matsuno, Y., Kusumoto-Matsuo, R. et al. GLI1 confers resistance to PARP inhibitors by activating the DNA damage repair pathway. Oncogene 43, 3037–3048 (2024). https://doi.org/10.1038/s41388-024-03105-1

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