Abstract
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 in vitro sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its in vivo activity. 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. 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.
Highlights
Bladder cancer is the most common malignancy of the urinary tract [1]
Six different bladder cancer cell lines of known genomic characteristics [5637 and J82 (RB1 mutant) and RT112, 253J, UM-UC-1 and RT4 (RB1 wt)], and representative of various tumor stages and bladder cancer subtypes [13], displayed a similar sensitivity to CDK4/6 inhibitor in a range of concentrations similar to those reported for other tumor cells
We observed that treated cells presented differences in their cellcycle profiles: while RB1 wt cells had a marked reduction in the percentage of S-phase entry with cells arresting in G1, RB1-mutant cells displayed a prominent reduction of G2–M phase entry and a significant induction of apoptosis
Summary
Bladder cancer is the most common malignancy of the urinary tract [1]. Two major classes of bladder cancer are distinguished [2]: approximately 75% of patients present a nonmuscle–invasive disease (NMIBC, stage Ta, T1 or CIS), while the. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Martínez-Fernandez: Mobile Genomes and Disease Lab, CIMUS, Universidade de Santiago de Compostela, Barcelona, Spain; current address for F. Villacampa, Urology Department, Clínica Universidad de Navarra, Madrid, Spain; and current address for S. Laboratory of Genome Integrity, NCI, NIH, Bethesda, Maryland
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