Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer
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ORIGINAL ARTICLE
Combination of cyclin‑dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer Qilai Long1,2 · Ai‑Hong Ma3 · Hongyong Zhang1 · Zhixiu Cao1,4 · Roger Xia1,5 · Tzu‑Yin Lin1 · Guru P. Sonpavde6 · Ralph de Vere White7 · Jianming Guo2 · Chong‑Xian Pan1,7,8,9 Received: 1 February 2020 / Accepted: 13 May 2020 © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 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 antiPD1 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. Keywords CDK4/6 · Targeted therapy · Chemotherapy · Immunotherapy · Bladder cancer · Patient-derived xenograft Qilai Long and Ai-Hong Ma contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02609-5) contains supplementary material, which is available to authorized users. * Jianming Guo guo.jianming@zs‑hospital.sh.cn
4
Department of Urology, Renmin Hospital, Wuhan University, Wuhan 430060, Hubei Province, China
* Chong‑Xian Pan [email protected]
5
Davis Senior High School, Davis, CA 95616, USA
6
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
7
Department of Urology, University of California Davis
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