The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecular factors conferring resistance to CDK4/6 inhibition in bladder cancer (BLCA) that also included components within the DNA repair pathway. In this study, we validated whether a combinatory treatment approach of the CDK4/6 inhibitor Palbociclib with Poly-(ADP-Ribose) Polymerase (PARP) inhibitors improves therapy response in BLCA. First, a comparison of PARP inhibitors Talazoparib and Olaparib showed superior efficacy of Talazoparib in vitro and displayed high antitumor activity in xenografts in the chicken chorioallantoic membrane (CAM) model. Moreover, the combination of Talazoparib and the CDK4/6 inhibitor Palbociclib synergistically reduced tumor growth in Retinoblastoma protein (RB)-positive BLCA in vitro and in a CAM model, an effect that relies on Palbociclib-induced cell cycle arrest in G0/G1-phase complemented by a G2 arrest induced by Talazoparib. Interestingly, Talazoparib-induced apoptosis was reduced by Palbociclib. The combination of Palbociclib and Talazoparib effectively enhances BLCA therapy, and RB is a molecular biomarker of response to this treatment regimen.
机构:
Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Fudan Univ, Zhongshan Hosp, Dept Urol, Shanghai 200032, Peoples R ChinaUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Long, Qilai
Ma, Ai-Hong
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Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Sacramento, CA 95817 USAUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Ma, Ai-Hong
Zhang, Hongyong
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Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USAUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Zhang, Hongyong
Cao, Zhixiu
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机构:
Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Wuhan Univ, Renmin Hosp, Dept Urol, Wuhan 430060, Hubei, Peoples R ChinaUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Cao, Zhixiu
Xia, Roger
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h-index: 0
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Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Davis Senior High Sch, Davis, CA 95616 USAUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Xia, Roger
Lin, Tzu-Yin
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Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USAUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Lin, Tzu-Yin
Sonpavde, Guru P.
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机构:
Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USAUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Sonpavde, Guru P.
White, Ralph de Vere
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Univ Calif Davis, Dept Urol, Canc Ctr, Sacramento, CA 95817 USAUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
White, Ralph de Vere
Guo, Jianming
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Fudan Univ, Zhongshan Hosp, Dept Urol, Shanghai 200032, Peoples R ChinaUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Guo, Jianming
Pan, Chong-Xian
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h-index: 0
机构:
Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
Univ Calif Davis, Dept Urol, Canc Ctr, Sacramento, CA 95817 USA
VA Northern Calif Hlth Care Syst, 10535 Hosp Way, Mather, CA 95655 USA
Harvard Med Sch, Med, West Roxbury, MA 02132 USAUniv Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
机构:
Shenzhen Univ, Affiliated Luohu Hosp, Inst Urol, Shenzhen 518000, Peoples R China
Shenzhen Tradit Chinese Med Hosp, Sci & Educ Dept, Shenzhen 518033, Peoples R China
Shenzhen Baoan Peoples Hosp, Dept Oncol, Shenzhen 518101, Peoples R ChinaShenzhen Univ, Affiliated Luohu Hosp, Inst Urol, Shenzhen 518000, Peoples R China
Kong, Chenfan
Sun, Jianrong
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机构:
Shenzhen Tradit Chinese Med Hosp, Dept Oncol, Shenzhen 518033, Peoples R ChinaShenzhen Univ, Affiliated Luohu Hosp, Inst Urol, Shenzhen 518000, Peoples R China
Sun, Jianrong
Hu, Xinzi
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h-index: 0
机构:
Shenzhen Baoan Peoples Hosp, Dept Oncol, Shenzhen 518101, Peoples R ChinaShenzhen Univ, Affiliated Luohu Hosp, Inst Urol, Shenzhen 518000, Peoples R China
Hu, Xinzi
Li, Guangzhi
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h-index: 0
机构:
Shenzhen Univ, Affiliated Luohu Hosp, Inst Urol, Shenzhen 518000, Peoples R ChinaShenzhen Univ, Affiliated Luohu Hosp, Inst Urol, Shenzhen 518000, Peoples R China
Li, Guangzhi
Wu, Song
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h-index: 0
机构:
Shanghai Univ Tradit Chinese Med, Affiliated Shenzhen Hosp, Dept Urol, Shenzhen 518000, Peoples R ChinaShenzhen Univ, Affiliated Luohu Hosp, Inst Urol, Shenzhen 518000, Peoples R China
机构:
Fudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Breast Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Zhu, Xiuzhi
Chen, Li
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机构:
Fudan Univ, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Breast Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Chen, Li
Huang, Binhao
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h-index: 0
机构:
Fudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Gastr Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Huang, Binhao
Li, Xiaoguang
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h-index: 0
机构:
Fudan Univ, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Breast Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Li, Xiaoguang
Yang, Liu
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机构:
Fudan Univ, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Breast Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Yang, Liu
Hu, Xin
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h-index: 0
机构:
Fudan Univ, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Breast Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Precis Canc Med Ctr, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Hu, Xin
Jiang, Yizhou
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h-index: 0
机构:
Fudan Univ, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Breast Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Jiang, Yizhou
Shao, Zhimin
论文数: 0引用数: 0
h-index: 0
机构:
Fudan Univ, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Dept Breast Surg, Shanghai Canc Ctr, 270 Dong An Rd, Shanghai 200032, Peoples R China
Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
Shao, Zhimin
Wang, Zhonghua
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机构:
Fudan Univ, Dept Breast Surg, Key Lab Breast Canc Shanghai, Shanghai Canc Ctr, Shanghai 200032, Peoples R ChinaFudan Univ, Shanghai Med Coll, Dept Oncol, 130 Dong An Rd, Shanghai 200032, Peoples R China
机构:
Univ Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, AustraliaUniv Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, Australia
De Ieso, Michael L.
Aldoghachi, Ahmed Faris
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Univ Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, AustraliaUniv Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, Australia
Aldoghachi, Ahmed Faris
Tilley, Wayne D.
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机构:
Univ Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, AustraliaUniv Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, Australia
Tilley, Wayne D.
Dwyer, Amy R.
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Univ Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, AustraliaUniv Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, Australia