Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Schubert, Nil A.; Schild, Linda; Oirschot, Stijn van; Keller, KM; Alles, Lindy K.; Vernooij, Lindy; Nulle, Marloes; Dolman, M. Emmy M.; Boogaard, Marlinde L. van den; Molenaar, Jan J.

doi:10.1016/j.ejca.2020.10.009

Cited by 10 publications

(13 citation statements)

References 45 publications

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“…The two cell lines with co-amplification of MDM2 and CDK4 displayed sensitivity to both MDM2i and CDK4/6i at levels like those of other p53 wt cell lines (Table 3 ), indicating that directed therapy could be beneficial, despite the amplification and overexpression of the respective target genes. The combination of MDM2i and CDK4i did not present synergetic effects concordant with a recent study of combined MDM2/CDK4i in NB 52 . According to the overall synergy score, a positive additive effect was found in p53 wt cell lines, including the MDM2/CDK4-amplified cell lines, even though non synergetic effect was detected.…”

Section: Discussionsupporting

confidence: 91%

“…WGS was performed on from three patients with tumors displaying 12q amplification, as evaluated from SNP microarrays. DNA from tumor material and matched constitutional DNA were subjected to sequencing and bioinformatical handling as described previously 52 Briefly, sequencing was performed on Illumina instrumentation (Illumina, San Diego, CA) at Clinical Genomics, SciLife Laboratories, Stockholm, Sweden for average read depths of 62, 32, and 74 for tumor samples 45R1, 59R9, and 73R6, respectively, and of 30, 36, and 36 for constitutional DNA, respectively. Mapping, realignment around indels, and variant calling were carried out using the Sentieon suite of bioinformatics tools (Sentieon Inc., Mountain View, CA) (Sentieon version v201808.03).…”

Section: Methodsmentioning

confidence: 99%

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Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup

Martinez-Monleon

Öberg

Gaarder

et al. 2022

Sci Rep

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In neuroblastoma, MYCN amplification and 11q-deletion are important, although incomplete, markers of high-risk disease. It is therefore relevant to characterize additional alterations that can function as prognostic and/or predictive markers. Using SNP-microarrays, a group of neuroblastoma patients showing amplification of one or multiple 12q loci was identified. Two loci containing CDK4 and MDM2 were commonly co-amplified, although amplification of either locus in the absence of the other was observed. Pharmacological inhibition of CDK4/6 with ribociclib or abemaciclib decreased proliferation in a broad set of neuroblastoma cell lines, including CDK4/MDM2-amplified, whereas MDM2 inhibition by Nutlin-3a was only effective in p53wild-type cells. Combined CDK4/MDM2 targeting had an additive effect in p53wild-type cell lines, while no or negative additive effect was observed in p53mutated cells. Most 12q-amplified primary tumors were of abdominal origin, including those of intrarenal origin initially suspected of being Wilms’ tumor. An atypical metastatic pattern was also observed with low degree of bone marrow involvement, favoring other sites such as the lungs. Here we present detailed biological data of an aggressive neuroblastoma subgroup hallmarked by 12q amplification and atypical clinical presentation for which our in vitro studies indicate that CDK4 and/or MDM2 inhibition also could be beneficial.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup

Martinez-Monleon

Öberg

Gaarder

et al. 2022

Sci Rep

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“…Synergistic interaction with ribociclib was also found for MEK1/2 inhibition [79]. In contrast, combined drugging of CDK4/6 and MDM2 activity did not show noticeable synergistic effects [80].…”

Section: Cdk4/ccnd1mentioning

confidence: 93%

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

Decaesteker

Durinck

Roy

et al. 2021

JPM

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Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities.

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“…In our previous study, we showed that CDKN2A-deleted cell lines do not respond be}er to MDM2 or CDK4/6 inhibiMon 20 . In line with these findings, our current compound sensiMvity screening revealed that none of the knockouts significantly influences sensiMvity to the four MDM2 and the three CDK4/6 inhibitors from the library (Supplementary Fig.…”

Section: Loss Of P16 Increases Sensi6vity To Egfr Inhibitorsmentioning

confidence: 95%

Loss of p16INK4a in neuroblastoma cells induces shift to an immature state with mesenchymal characteristics and increases sensitivity to EGFR inhibitors

Schubert

Hooff

Schild

et al. 2021

Preprint

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Homozygous inactivation of the CDKN2A locus is one of the most common genomic aberrations in human cancer. The locus codes for two unrelated and distinctly regulated proteins: p14ARF and p16INK4a, which inhibit MDM2 and CDK4/6, respectively. Loss of CDKN2A is also a recurrent event in relapsed neuroblastoma, a childhood tumour that arises from neural crest cells. To examine the consequences of the loss of the two distinct gene transcripts in neuroblastoma, we used the CRISPR-Cas9 system to knockout p14, p16 and p14+p16 in SY5Y cells. RNA sequencing of the transcriptome revealed a striking shift towards an immature Schwann cell precursor-like phenotype with mesenchymal characteristics, specifically in the p16 and p14+p16 knockouts. High-throughput drug screening of p16 and p14+p16 knockout clones identified a large increase in sensitivity to EGFR inhibitors. On protein level, we were able to confirm that EGFR pathway activation is higher in p14+p16 knockout cells and that treatment with the EGFR inhibitor afatinib resulted in higher levels of apoptosis. Afatinib also reduced tumour growth in vivo in xenografts transplanted with p14+p16 knockout SY5Y cells. Overall, our study suggests that CDKN2A deletion in neuroblastoma relates to a phenotypic shift towards a more progenitor like state and increases sensitivity to EGFR inhibitors.

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Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

Cited by 10 publications

References 45 publications

Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup

Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

Loss of p16INK4a in neuroblastoma cells induces shift to an immature state with mesenchymal characteristics and increases sensitivity to EGFR inhibitors

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