AURKA and PLK1 inhibition selectively and synergistically block cell cycle progression in diffuse midline glioma

Targeting the Complex Protein Network of MYCN-amplified Anaplastic Ependymoma: A Case Report

“…Both kinases perpetrate signaling cascades that activate other transcription factors, including glioma-associated oncogene zinc finger protein (GLI1), hypoxia-inducible factor 1-alpha (HIF1A), zinc finger E-box-binding homeobox 1 (ZEB1), JUN, and FOXM1 by PLK1, and YAP1, nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB), Forkhead box protein O1 (FOXO1), and signal transducer and activator of transcription 3 (STAT3) by AURKA to drive malignant behavior. Not surprisingly, laboratory models show that simultaneous inhibition of PLK1 and AURKA produces synergistic anti-tumor activity compared to targeting either kinase alone [56,57]. Based on these contemporary signaling pathway insights, co-targeting both PLK1 and AURKA targeting may be the minimum combinatorial strategy needed for approaching MYCN-driven cancers.…”

Clustered regularly interspaced short palindromic repeats screens in pediatric tumours: A review

“…A patient-derived tumour model derived from AT/RT in custom enriched culturing conditions was used by Metselaar et al where they used three different cell lines to investigate synthetic lethality with an Aurora kinase A (AURKA) inhibitor, phtalazinone pyrazole. 57 The authors aimed to identify true synergistic hits from genetic knockouts to which the tumour cell could easily adapt, by collecting DNA at multiple time points during the screen. The synergistic hit followed up by the authors (polo-like kinase 1 [PLK1]) was present in all timepoints, but genes related to AURKA inhibition, for example, AURKB and BUB1B, were a hit after 14 days of treatment but not after 21 days, suggesting resistance or at least circumvention of this pathway.…”

“…Most publications are based on experiments performed in serum-cultured cell lines, but some publications used primary patient-derived cell lines for CRISPR screens. [55][56][57] Some of the CRISPR screens included in this review have used published data from the DepMap consortium or were a part of this consortium. 48,58 The majority of CRISPR screens were performed in leukaemia or neuroblastoma tumour cells, which does not reflect the incidence distribution of pediatric cancers, as CNS tumours are nearly as common as leukaemias in children.…”

“…For this review we selected CRISPR screens performed in pediatric tumour cell lines, using an algorithm of “CRISPR” and “screen” mentioned in either title or abstract and selected those publications using human pediatric tumour models in PubMed. Most publications are based on experiments performed in serum‐cultured cell lines, but some publications used primary patient‐derived cell lines for CRISPR screens 55–57 . Some of the CRISPR screens included in this review have used published data from the DepMap consortium or were a part of this consortium 48,58 …”

“…A patient‐derived tumour model derived from AT/RT in custom enriched culturing conditions was used by Metselaar et al. where they used three different cell lines to investigate synthetic lethality with an Aurora kinase A (AURKA) inhibitor, phtalazinone pyrazole 57 . The authors aimed to identify true synergistic hits from genetic knockouts to which the tumour cell could easily adapt, by collecting DNA at multiple time points during the screen.…”