Sensitivity of Glioblastomas to Clinically Available MEK Inhibitors Is Defined by Neurofibromin 1 Deficiency

See, Wendy L.; Tan, I-Li; Mukherjee, Joydeep; Nicolaides, Theodore; Pieper, Russell O.

doi:10.1158/0008-5472.can-12-0334

Cited by 87 publications

(84 citation statements)

References 37 publications

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“…Previous work has shown that NF1 -deficient GBM cells have variable degrees of MEK inhibitor sensitivity (See et al, 2012). This relative MEK inhibitor sensitivity was also observed in o-GSCs, which results from MEK/CRAF binding and CRAF activation such that treatment with a MEK inhibitor (trametinib) that additionally promotes the dissociation of MEK from CRAF effectively blocked o-GSC growth.…”

Section: Discussionmentioning

confidence: 99%

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

et al. 2015

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Summary The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis-1 (Nf1) genetically-engineered mouse LGG model, we report the isolation of CD133+ multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently-employed conventional and biologically-targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomal analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against endoplasmic reticulum (ER) stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

et al. 2015

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“…Pharmacodynamic analyses of intratumoral MAPK, PI3K and mTOR signaling were not completed leaving the cause of the lack of efficacy unresolved (46-48). Other agents, possibly those directly inhibiting Raf[mgn]MEK[mgn]Erk signal cascades, such as the MEK inhibitor AZD6244, may also curtail ON123300-induced Erk activation (49, 50); however with the gefitinib-ON123300 combination not only was Erk activation suppressed Akt inhibition was enhanced.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Zhang

Zhou

et al. 2014

Molecular Cancer Therapeutics

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ON123300 is a low molecular weight multi-kinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochemical assays indicated ON123300 was a strong inhibitor of Ark5 and CDK4 as well as growth factor receptor tyrosine kinases such as Beta-type platelet-derived growth factor receptor [PDGFRβ]. ON123300 inhibited U87 glioma cell proliferation with an IC50 = 3.4 ± 0.1 μM and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation; both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K initiated PI3K negative feedback loop. Co-treatment with the EGFR inhibitor gefitinib [GFN] produced synergistic cytotoxic effects. Pursuant to the in vitro studies, in vivo pharmacokinetic [PK] and pharmacodynamic [PD] studies of ON123300 were completed in mice bearing intracerebral U87 tumors following IV doses of 5 mg/kg and 25 mg/kg alone, and also at the higher dose concurrently with GFN. ON123300 showed high brain and brain tumor accumulation based on brain partition coefficient values of at least 2.5. Consistent with the in vitro studies, single agent ON123300 caused a dose-dependent suppression of phosphorylation of Akt as well as activation of Erk in brain tumors, whereas addition of GFN to the ON123300 regimen significantly enhanced p-Akt inhibition and prevented Erk activation. In summary, ON123300 demonstrated favorable PK characteristics and future development for brain tumor therapy would require use of combinations, such as GFN, that mitigated its Erk activation and enhanced its activity.

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“…This may indicate that other tumors driven by NF1 loss, including PA associated with neurofibromatosis, may be amenable to small molecule inhibition of downstream targets in the MAPK pathway (8). …”

Section: Introductionmentioning

confidence: 99%

Current Understanding of BRAF Alterations in Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade Gliomas

et al. 2015

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The mitogen-activated protein kinase (MAPK) pathway is known to play a key role in the initiation and maintenance of many tumors as well as normal development. This often occurs through mutation of the genes encoding RAS and RAF proteins which are involved in signal transduction in this pathway. BRAF is one of three RAF kinases which act as downstream effectors of growth factor signaling leading to cell cycle progression, proliferation, and survival. Initially reported as a point mutation (V600E) in the majority of metastatic melanomas, other alterations in the BRAF gene have now been reported in a variety of human cancers including papillary thyroid cancer, colon carcinomas, hairy cell leukemia, and more recently in gliomas. The identification of oncogenic mutations in the BRAF gene have led to a revolution in the treatment of metastatic melanoma using targeted molecular therapies that affect the MAPK pathway either directly through BRAF inhibition or downstream through inhibition of MEK. This review describes the molecular biology of BRAF in the context of pediatric low-grade gliomas, the role of BRAF as a diagnostic marker, the prognostic implications of BRAF, and evidence for therapeutic targeting of BRAF.

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Sensitivity of Glioblastomas to Clinically Available MEK Inhibitors Is Defined by Neurofibromin 1 Deficiency

Cited by 87 publications

References 37 publications

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Current Understanding of BRAF Alterations in Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade Gliomas

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