Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

Schubert, Nil A.; Chen, Celine; Rodríguez, Ana Isabel Enríquez; Koster, Jan; Dowless, Michele; Pfister, Stefan M.; Shields, David J.; Stancato, Louis F.; Vassal, Gilles; Caron, Hubert; Boogaard, Marlinde L. van den; Henssen, Anton; Molenaar, Jan J.

doi:10.1016/j.ejca.2022.04.028

Cited by 9 publications

(8 citation statements)

References 61 publications

(76 reference statements)

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“…In line with Schubert et al (2022) [ 391 ], CDK4/6 upregulation also plays an important role in the pathogenesis and progression of high-grade gliomas with potential actionability [ 407 , 408 , 409 ]. However, the use of CDK4/6 inhibitors alone did not show satisfactory results, suggesting the use of combinatorial intervention [ 410 ].…”

Section: Protein Kinases In Pediatric Oncology and Their Association ...supporting

confidence: 55%

“…Activation of the CDK4/6 pathway is also a powerful driver of sarcomagenesis [ 391 ]. Amplification of 12q13-15 also occurs in OS, and a recent copy number analysis of pediatric high-grade OS detected a recurrent gain of chromosome 12q14.1 in ~25% of samples, which resulted in CDK4 overexpression.…”

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

“…More recently, a systematic evaluation of CDK4/6 as targets in a series 16 pediatric cancer types indicated that further preclinical evaluations are still needed to affirm the dependence of tumors on CDK4/6. Nevertheless, the results provided evidence for benefits in EWS, malignant peripheral nerve sheath tumors and MB [ 391 ]. Of note, within MB subgroups, CDK6 and CDK14 co-amplifications were identified in 20% samples from patients with relapsed group-4 MB [ 330 ].…”

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

“…Shubert et al (2022) also pointed out that patients with atypical rhabdoid tumor/malignant rhabdoid tumor, NB or HGG may also benefit from anti-CDK4/6 therapy [ 391 ].…”

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

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Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

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Section: Protein Kinases In Pediatric Oncology and Their Association ...supporting

confidence: 55%

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

“…Shubert et al (2022) also pointed out that patients with atypical rhabdoid tumor/malignant rhabdoid tumor, NB or HGG may also benefit from anti-CDK4/6 therapy [ 391 ].…”

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

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Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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“…The highly selective CDK4 inhibitors, such as Palbociclib and Ribociclib, have already shown signi cant antitumor activity against NB in several pre-clinical or clinical trials [9][10][11]. These compounds can lead to competitive inhibition of active CDK4 via interacting with the ATP-binding pocket of CDK4.…”

Section: Introductionmentioning

confidence: 99%

Autophagic degradation of CDK4 is responsible for G0/G1 cell cycle arrest in NVP-BEZ235-treated neuroblastoma

Liu

Wang

et al. 2023

Preprint

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CDK4 is highly expressed and correlated with poor prognosis and decreased survival in advanced NB. Seeking a regimen that selectively targets CDK4 degradation is a potentially promising therapeutic strategy relative to conventional CDK4 inhibitors.In this work, we determined that autophagy as a new pathway for the degradation of CDK4. Firstly, autophagic degradation of CDK4 is critical for NVP-BEZ235-induced G0/G1 arrest and growth inhibition via the blockade of autophagy-related gene Beclin1. Secondly, we observed the first evidence that the p62 binds to CDK4 and then enter autophagolysosome to degradate CDK4 in a CTSB-dependent manner in NVP-BEZ235 treated NB cells. Analogous results regarding the interaction p62 with CDK4 were observed in NVP-BEZ235 treated neuroblastoma xenograft mouse model. These results not only established the pivotal role of the autophagy pathway in CDK4 turnover but also suggest the potential application of NVP-BEZ235 or other drugs via the therapeutic modulation of autophagic degradation of CDK4 protein in NB.

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Therapeutic SHPRH-146aa encoded by circ-SHPRH dynamically upregulates P21 to inhibit CDKs in neuroblastoma

Chang,

Ren,

Zhang

et al. 2024

Cancer Letters

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Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

Cited by 9 publications

References 61 publications

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Autophagic degradation of CDK4 is responsible for G0/G1 cell cycle arrest in NVP-BEZ235-treated neuroblastoma

Therapeutic SHPRH-146aa encoded by circ-SHPRH dynamically upregulates P21 to inhibit CDKs in neuroblastoma

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