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01-11-2020 | Cytostatic Therapy | Original Article

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

Authors: Qilai Long, Ai-Hong Ma, Hongyong Zhang, Zhixiu Cao, Roger Xia, Tzu-Yin Lin, Guru P. Sonpavde, Ralph de Vere White, Jianming Guo, Chong-Xian Pan

Published in: Cancer Immunology, Immunotherapy | Issue 11/2020

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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Title: Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer
Authors: Qilai Long
Ai-Hong Ma
Hongyong Zhang
Zhixiu Cao
Roger Xia
Tzu-Yin Lin
Guru P. Sonpavde
Ralph de Vere White
Jianming Guo
Chong-Xian Pan
Publication date: 01-11-2020
Publisher: Springer Berlin Heidelberg
Keyword: Cytostatic Therapy
Published in: Cancer Immunology, Immunotherapy / Issue 11/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02609-5

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Abstract

Background

Methods

Results

Conclusions

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