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

Abstract

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. , and PIE 15/00076 and CB/16/00228 (to J.M. Paramio); FEDER cofounded MINECO ISCIII grant PI15/00993 (to M. Santos); FEDER cofounded MINECO grants SAF2013-49147-P and SAF2016-80874-P and Ramon y Cajal contract RYC-2011-09242 (to S. Ruiz); and a grant from Asociaci on Española contra el C ancer Rubio et al.

Differential development of large-cell neuroendocrine or small-cell lung carcinoma upon inactivation of 4 tumor suppressor genes

“…We used 2 different approaches: on the one hand we used conventional cytomegalovirus promoter, Ad5-CMVcre, which targets most lung cell types (17) ( SI Appendix , Fig. S1 A – E ); on the other hand, we used an adenovirus (Ad5-K5cre) in which cre recombinase is under the control of keratin K5 promoter (18). This approach is based on the ability of proximal airway basal cells to self-renew and give rise to other cellular types (6, 7, 19) and has been reported to target lung basal cells (8).…”

Targeted Molecular Therapy in Palliative Cancer Management

“…The authors concluded that the bladder cancer cells lines were sensitive to CDK4/6 inhibition regardless of RB status, suggesting a novel pathway. In the mouse model, CDk4/6 inhibition correlated with FOXM1 knockdown, and FOXM1 is an oncogenic driver in bladder cancer [125]. This study warrants further exploration of CDK4/6 inhibitors in bladder cancer in human studies, and also research into the link between CDK4/6 inhibitors and FOXM1 knockdown, which shows promise as a novel therapeutic tool.…”

How selective are clinical CDK4/6 inhibitors?

“…Levels of FOXM1 correlated with sensitivity to CDK4/6 inhibitors in Rb‐deficient bladder and small‐cell lung cancer cell lines. This observation led to a breakthrough in the treatment of advanced bladder cancer, which was previously considered unfit for treatment using existing drugs 85 …”