Metastatic bladder cancer is treated, in most cases, by cystectomy and platinum-based chemotherapy. Various targeted therapies are being clinically and preclinically tested for bladder cancer management. Metastatic bladder cancer has been associated with loss of cell cycle control. TCGA analysis also revealed that TP53 mutations were mutually exclusive in their relationship with overexpression and amplification of MDM2, thereby resulting in inactivation of p53 function in 76% of samples. Defects in the RB pathway are another major mechanisms by which cell cycle control is lost in metastatic bladder cancer. 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.
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 bladder cancer cell lines of known genomic characteristics and differing in their RB1 status, were tested for their sensitivity to palbociclib.
Unexpectedly, we observed a similar response to palbociclib in pRb wt and pRb mutant cell lines in vitro and in xenografts in vivo, although with different biochemical and cell cycle effects. Genomic characterization of these treated cells shows strong gene expression divergence as a consequence of palbociclib treatment in pRb wt and mutant cells. Nonetheless, bioinformatic analyses revealed FoxM1 as a possible common regulator of some downregulated genes in both cases. Importantly, FoxM1 has been demonstrated a bona fide cdk4 substrate and may confer cis-platinum resistance. We observed reduced FoxM1 phosphorylation upon palbociclib treatment in all cell lines tested, and also increased sensitivity to cis-platinum. Remarkably, we found that phosphorylated FoxM1 is a potential poor prognosis factor in human bladder cancer clinical samples.
in our study we observed that the activity of palbociclib in bladder cancer cell lines described is indepedently of the RB1 status and showed synergistic activity with cisplatin. Future studies, using mouse models based on the genetic inactivation of Rb1 with other tumor suppressor genes, will precede the possible development of appropriate clinical trials testing the use of palbociclib in the management of bladder cancer patients.
Clinical trial indentification
Legal entity responsible for the study
I + 12 Research Institute
All authors have declared no conflicts of interest.