CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status
Carolina Rubio # 1 2 , Mónica Martínez-Fernández # 1 2 3 , Cristina Segovia 1 2 3 , Iris Lodewijk 1 3 , Cristian Suarez-Cabrera 1 , Carmen Segrelles 1 2 3 , Fernando López-Calderón 3 , Ester Munera-Maravilla 1 3 , Mirentxu Santos 1 2 3 , Alejandra Bernardini 1 2 3 , Ramón García-Escudero 1 2 3 , Corina Lorz 1 2 3 , Maria José Gómez-Rodriguez 1 2 , Guillermo de Velasco 1 , Irene Otero 1 , Felipe Villacampa 1 2 , Felix Guerrero-Ramos 1 , Sergio Ruiz 4 , Federico de la Rosa 1 2 , Sara Domínguez-Rodríguez 5 , Francisco X Real 2 6 7 , Núria Malats 2 5 , Daniel Castellano 1 2 , Marta Dueñas 1 2 3 , Jesus M Paramio 8 2 3
Purpose: 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).
Experimental design: Bladder cancer cell lines were tested for in vitro sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its in vivo activity.
Results: Cell lines tested were sensitive to CDK4/6 inhibition, independent on RB1 gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation in vitro and in vivo and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer.
Conclusions: 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.