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Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer

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Abstract

Background

Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer

Methods

The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug–drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy.

Results

Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models.

Conclusions

The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.

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Availability of data and materials

All data generated or analyzed during this study are included in this article and its supplementary information file.

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Acknowledgements

We would like to thank Dr. Aminah Ikner and Dr. Paul Henderson for help during manuscript preparation.

Funding

Work was supported in part by U54 Grant (Grant No: 1 U54 CA233306; Contact PI: Pan), R01 Grant (Grant No: 1R01CA176803-01; PI: Pan), Merit Review (Award # 1I01 BX003840, PI: Pan) from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Program. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Author information

Author notes

  1. Chong-Xian Pan

    Present address: Medicine, Harvard Medical School, West Roxbury, MA, 02132, USA

  2. Qilai Long and Ai-Hong Ma contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA

    Qilai Long, Hongyong Zhang, Zhixiu Cao, Roger Xia, Tzu-Yin Lin & Chong-Xian Pan

  2. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Qilai Long & Jianming Guo

  3. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA

    Ai-Hong Ma

  4. Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei Province, China

    Zhixiu Cao

  5. Davis Senior High School, Davis, CA, 95616, USA

    Roger Xia

  6. Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Guru P. Sonpavde

  7. Department of Urology, University of California Davis Cancer Center, Sacramento, CA, 95817, USA

    Ralph de Vere White & Chong-Xian Pan

  8. VA Northern California Health Care System, 10535 Hospital Way, Mather, CA, 95655, USA

    Chong-Xian Pan

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Contributions

QL and AHM designed and performed experiments, analyzed data, and contributed to writing the paper; HZ, ZC, and RX performed experiments and analyzed data; TYL, GPS, RDW, and JG provided essential experimental tools and support; CXP designed the investigation, analyzed data, supervised the study, and wrote the paper. All authors read and approved the manuscript as submitted.

Corresponding authors

Correspondence to Jianming Guo or Chong-Xian Pan.

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In vivo studies were approved by the Institutional Animal Care and Use Committee.

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Long, Q., Ma, AH., Zhang, H. et al. Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer. Cancer Immunol Immunother 69, 2305–2317 (2020). https://doi.org/10.1007/s00262-020-02609-5

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