Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma

Abstract

Purpose Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes. Experimental Procedures We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011, a highly specific CDK4/6 inhibitor. Results Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nM in sensitive lines). LEE011 caused cell cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. While our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (p = 0.01), the identification of additional clinically accessible biomarkers is of high importance. Conclusions Taken together, our data show that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease.

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

“…previously linked to ribociclib sensitivity in neuroblastomaderived cell lines (16). There were no discernible differences between the genetic profile of patients who had SD and those who had disease progression in patients who had neuroblastoma or MRT.…”

“…None of these pediatric tumors exhibited CCND1 gene amplification, an alteration found in 2 of 3 cancers in adult patients who experienced an objective tumor response to ribociclib. In addition, only one patient with progressive disease exhibited MYCN amplification, an alteration associated with ribociclib sensitivity in preclinical studies of neuroblastoma (16). It must be noted that the NGS analysis was performed on a limited number of patient samples, and the association between CCND1 or MYCN amplification and treatment response could therefore not be evaluated.…”

“…In addition, ribociclib caused cell-cycle arrest and senescence in a series of human neuroblastoma-derived cell lines (particularly those harboring MYCN amplification; ref. 16), and treatment of both neuroblastoma and MRT subcutaneous xenograft models resulted in tumor growth delays (15,16). Collectively, these findings led to the hypothesis that ribociclib may have activity in neuroblastoma and MRTs with CDK4/6 activation through p16 loss or CCND1, CDK4, or CDK6 amplification.…”

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

“…Here, we report the results of a screening strategy developed to identify pro-senescence compounds acting on a specific and relevant genetically defined subset of cancers, such as PTEN null tumours. The validity of this approach is supported by the effective identification of druggenotype associations already established in previous preclinical models 26,40,41 and from the identification of CK2 inhibitors that show high selectivity in PTEN-deficient cells and tumours. Our screening approach coupling a small-molecule screening with a shRNA screen has allowed us to focus on a target that has been identified in both the screens, using complementary methodologies.…”

Does CDKN2A Loss Predict Palbociclib Benefit?

“…Phase i studies have determined a maximum tolerated dose of 200 mg every 12 hours for abemaciclib 7 Recently, another cdk 4/6 inhibitor, ribociclib, has been shown to have activity in neuroblastoma cell lines 8 . It is also being actively studied in patients with advanced hr-positive, her2-negative breast cancer in combination with letrozole, and in premenopausal women combined with goserelin plus tamoxifen compared with an aromatase inhibitor (https://clinicaltrials.gov/ct2/show/NCT01919229, https://clinicaltrials.gov/ct2/show/NCT01958021, https:// clinicaltrials.gov/ct2/show/NCT02422615, and https:// clinicaltrials.gov/ct2/show/NCT02278120).…”