Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event

Koschmann, Carl; Farooqui, Zishaan; Kasaian, Katayoon; Cao, Xuhong; Zamler, Daniel B.; Stallard, Stefanie; Venneti, Sriram; Hervey-Jumper, Shawn L.; Garton, Hugh; Muraszko, Karin M.; Franchi, L; Robertson, Patricia L.; Leonard, Marcia; Opipari, Valerie P.; Castro, Maria G.; Löwenstein, Pedro R.; Chinnaiyan, Arul M.; Mody, Rajen

doi:10.1038/s41698-017-0033-y

Cited by 20 publications

(18 citation statements)

References 33 publications

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“…Additionally, previous work from several groups has suggested that specific thresholds of replication stress may exists within different tumour populations that could exert important biological consequences for tumour development and growth and impact on further mutations/genetic alterations that facilitate tumour development [ 11 , 12 , 14 , 30 , 33 ]. Intriguingly, a recent report identified CNV gains and increased CDK18 mRNA expression in several distinct tumour populations from within a diffuse intrinsic pontine glioma, suggesting a selection preference for such genetic alterations to CDK18 expression during tumour development [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

et al. 2018

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BackgroundCyclin-Dependent Kinases (CDKs) are established anti-cancer drug targets and a new generation of CDK inhibitors are providing clinical benefits to a sub-set of breast cancer patients. We have recently shown that human CDK18 promotes efficient cellular responses to replication stress. In the current study, we have investigated the clinicopathological and functional significance of CDK18 expression levels in breast cancers.ResultsHigh CDK18 protein expression was associated with a triple negative and basal-like phenotype (p = 0.021 and 0.027 respectively) as well as improved patient survival, which was particularly significant in ER negative breast cancers (n = 594, Log Rank 6.724, p = 0.01) and those treated with chemotherapy (n = 270, Log Rank 4.575, p = 0.03). In agreement with these clinical findings, breast cancer cells genetically manipulated using a dCRISPR approach to express high levels of endogenous CDK18 exhibited an increased sensitivity to replication stress-inducing chemotherapeutic agents, as a consequence to defective replication stress signalling at the molecular level.ConclusionsThese data reveal that CDK18 protein levels may predict breast cancer disease progression and response to chemotherapy, and provide further rationale for potential targeting of CDK18 as part of novel anti-cancer strategies for human cancers.Materials and MethodsCDK18 protein expression was evaluated in 1650 breast cancers and correlated to clinicopathological parameters and survival outcomes. Similar analyses were carried out for genetic and transcriptomic changes in CDK18 within several publically available breast cancer cohorts. Additionally, we used a deactivated CRISPR/Cas9 approach (dCRISPR) to elucidate the molecular consequences of heightened endogenous CDK18 expression within breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

et al. 2018

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“…These data revealed a potentially important role for increased pAKT levels as a novel biomarker for predicting a reduced initial EGFR-TKI response in patients (26). Activation of AKT also predicted the development of diffuse intrinsic pontine gliomas based on the loss of PTEN (27). Nuclear pAKT (Ser473) Cyclin D1 WEE1 Bim Bcl-2 Bax Figure 1.…”

Section: Pakt As a Prognostic Marker In The Clinicmentioning

confidence: 91%

AKT as a Therapeutic Target for Cancer

et al. 2019

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Many cellular processes in cancer are attributed to kinase signaling networks. V-akt murine thymoma viral oncogene homolog (AKT) plays a major role in the PI3K/AKT signaling pathways. AKT is activated by PI3K or phosphoinositidedependent kinases (PDK) as well as growth factors, inflammation, and DNA damage. Signal transduction occurs through downstream effectors such as mTOR, glycogen synthase kinase 3 beta (GSK3b), or forkhead box protein O1 (FOXO1). The abnormal overexpression or activation of AKT has been observed in many cancers, including ovarian, lung, and pancreatic cancers, and is associated with increased cancer cell proliferation and survival. Therefore, targeting AKT could provide an important approach for cancer prevention and therapy. In this review, we discuss the rationale for targeting AKT and also provide details regarding synthetic and natural AKT-targeting compounds and their associated studies.

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“…[94] PTEN is an established negative regulator of PI3K signaling and an important tumor suppressor, [95] with functional loss shown to be an early event in DIPG, [93] however, it is not regarded as a driver mutation. [93] This pinpoints the PI3K/AKT/mTOR signaling axis as the most common network controlling oncogenic growth and survival in H3K27M mutant DIPG ( Figure 2).…”

Section: Phosphoinositide-3 Kinase/protein Kinase-b/mammalian Target mentioning

confidence: 99%

Signal Transduction in Diffuse Intrinsic Pontine Glioma

et al. 2019

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Diffuse intrinsic pontine glioma (DIPG) is an untreatable, heterogeneous high‐grade glioma (HGG) of the brainstem. This highly aggressive cancer affects mostly young children and is uniformly fatal. Genomic studies show that DIPG is driven by somatic mutations to histone H3, either H3.1 or H3.3 variants (HIST1H3B/C and H3F3A), altering the epigenetic landscape of primitive oligodendrocyte or astrocyte precursor cells of the pontine region of the brainstem. Lysine‐to‐methionine point mutations at amino acid 27 (H3K27M) co‐occur with alterations in signaling genes, including the receptor tyrosine kinases (PDGFR/KIT/VEGFR/MET/EGFR), activin A receptor (ACVR1), intracellular kinases (PI3K/AKT/mTOR), cyclin‐dependent kinases (CDKs1/4/6), transcriptional regulators (MYCN), and tumor suppressors (PTEN/TP53). This cooperation drives gene expression signatures that inhibit cellular differentiation (ID1/2, Hedgehog) and promotes malignant transformation. Unique to DIPG, is the frequency of co‐occurring sets of genomic insults. However, mapping of the oncogenic signaling pathways activated in response to recurring mutations is unresolved. Herein, known oncogenic signal pathways activated in response to recurring somatic mutations and gene amplifications in DIPG are reviewed. Additionally, an important role for high‐resolution quantitative proteomics/phosphoproteomics in the characterization of signaling cascades are highlighted. These regulate the cell cycle, epigenetics and anti‐apoptotic processes, information critical for the development of improved treatment strategies for DIPG.

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Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event

Cited by 20 publications

References 33 publications

The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

AKT as a Therapeutic Target for Cancer

Signal Transduction in Diffuse Intrinsic Pontine Glioma

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