RB-independent activity of Cdk4/6 in bladder cancer.

Abstract

e16011Background: MIBC is treated, in most cases, by cystectomy and platinum-based chemotherapy. Nonetheless, the metastatic spreading occurs very often with fatal consequences. Various targeted therapies are being clinically and preclinically tested for BC management. MIBC have been associated with loss of cell cycle control. Defects in the RB pathway are a major mechanisms of cell cycle deregulation in MIBC. RB1 mutations were reported in 13% of TCGA samples, although significant mutations also were noted in CDKN1A, CDKN2A, and CCND3. The CDK 4/6 complex combines with cyclin D1 to inhibit RB activity. Therapeutic targeting of this complex improves outcome in ER positive advanced breast cancer. Methods: Palbociclib (PD-0332991) is a cdk4/6 inhibitor currently tested for the treatment of other malignancies characterized by the presence of a functional RB1 gene. A series of BC cell lines of known genomic characteristics and differing in their RB1 status, were tested for their sensitivity to Palbociclib. Re...