Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer

Florian G Klein,Zhichao Tong,Jürgen E Gschwend,Per Sonne Holm,Roman Nawroth,Charlène Granier,Yuling Zhao,Qi Pan

doi:10.3390/jpm11050340

Abstract

The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecular factors conferring resistance to CDK4/6 inhibition in bladder cancer (BLCA) that also included components within the DNA repair pathway. In this study, we validated whether a combinatory treatment approach of the CDK4/6 inhibitor Palbociclib with Poly-(ADP-Ribose) Polymerase (PARP) inhibitors improves therapy response in BLCA. First, a comparison of PARP inhibitors Talazoparib and Olaparib showed superior efficacy of Talazoparib in vitro and displayed high antitumor activity in xenografts in the chicken chorioallantoic membrane (CAM) model. Moreover, the combination of Talazoparib and the CDK4/6 inhibitor Palbociclib synergistically reduced tumor growth in Retinoblastoma protein (RB)-positive BLCA in vitro and in a CAM model, an effect that relies on Palbociclib-induced cell cycle arrest in G0/G1-phase complemented by a G2 arrest induced by Talazoparib. Interestingly, Talazoparib-induced apoptosis was reduced by Palbociclib. The combination of Palbociclib and Talazoparib effectively enhances BLCA therapy, and RB is a molecular biomarker of response to this treatment regimen.

Highlights

Introduction published maps and institutional affilSmall-molecule inhibitors against cyclin-dependent kinase 4/6 (CDK4/6) are potent compounds for cancer treatment [1]
We further examined whether the combination of Poly-(ADP-Ribose) Polymerase (PARP) inhibitors and CDK4/6 inhibitors might function as a supportive mechanism for the treatment of bladder cancer (BLCA)
Three out of four genes belonging to the “resolution of apurinic/apyrimidinic site via single-nucleotide replacement pathway” were significantly enriched, indicating the involvement of DNA repair pathways in therapy response (Figure 1B)

Summary

Introduction

Small-molecule inhibitors against cyclin-dependent kinase 4/6 (CDK4/6) are potent compounds for cancer treatment [1]. CDK4/6 are kinases that regulate the cell cycle transition from G1- into S-phase. A recent comprehensive analysis of different molecular subtypes in a cohort of 412 muscle-invasive bladder cancers (BLCA) revealed that approximately 90% of these tumors displayed genetic alterations in regulatory elements of the cell cycle pathway [2]. Upon phosphorylation by CDK4/6, E2F is released from the RB/E2F inhibitory complex, activating the transcription of E2F-regulated proteins that initiate the cellular transition from G0/G1- to S-phase [4]. The antiproliferative potential of the CDK4/6 inhibitor Palbociclib in RB-positive BLCA cells has been shown [5,6]. Due to the complex network of cellular agonists and antagonists that regulate the activity iations

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