CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status

Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfi...

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Bibliographic Details
Published in:Clinical cancer research 2019-01, Vol.25 (1), p.390-402
Main Authors: Rubio, Carolina, Martínez-Fernández, Mónica, Segovia, Cristina, Lodewijk, Iris, Suarez-Cabrera, Cristian, Segrelles, Carmen, López-Calderón, Fernando, Munera-Maravilla, Ester, Santos, Mirentxu, Bernardini, Alejandra, García-Escudero, Ramón, Lorz, Corina, Gómez-Rodriguez, Maria José, de Velasco, Guillermo, Otero, Irene, Villacampa, Felipe, Guerrero-Ramos, Felix, Ruiz, Sergio, de la Rosa, Federico, Domínguez-Rodríguez, Sara, Real, Francisco X, Malats, Núria, Castellano, Daniel, Dueñas, Marta, Paramio, Jesus M
Format: Article
Language:English
Subjects:
Aged
Animals
Apoptosis - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Cisplatin - pharmacology
Cyclin-Dependent Kinase 4 - antagonists & inhibitors
Cyclin-Dependent Kinase 4 - genetics
Cyclin-Dependent Kinase 6 - antagonists & inhibitors
Cyclin-Dependent Kinase 6 - genetics
Female
Forkhead Box Protein M1 - genetics
Heterografts
Humans
Male
Mice
Neoplasm Recurrence, Local - drug therapy
Neoplasm Recurrence, Local - genetics
Neoplasm Recurrence, Local - pathology
Phosphorylation - drug effects
Progression-Free Survival
Protein Kinase Inhibitors - pharmacology
Retinoblastoma Binding Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Urinary Bladder Neoplasms - drug therapy
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - pathology
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Summary:Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP). Bladder cancer cell lines were tested for sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its activity. Cell lines tested were sensitive to CDK4/6 inhibition, independent on gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation and and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer. CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-18-0685