MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors

Jessen, Walter J.; Miller, Shyra J.; Jousma, Edwin; Wu, Jianqiang; Rizvi, Tilat A.; Brundage, Meghan E.; Eaves, David W.; Widemann, Brigitte C.; Kim, Miok; Dombi, Eva; Sabo, Jessica; Dudley, Atira Hardiman; Niwa‐Kawakita, Michiko; Page, Grier P.; Giovannini, Marco; Aronow, Bruce J.; Cripe, Timothy P.; Ratner, Nancy

doi:10.1172/jci60578

Cited by 282 publications

(263 citation statements)

References 64 publications

(81 reference statements)

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“…Thus, Schwann cells retrieved from neurofibromas exhibited increased cAMP levels (30,35). Activation of MEK/MAPK was also observed in the peripheral nerve sheath in one mouse model (36). Conversely, Nf1 +/− heterozygous mice showed decreased cAMP levels in astrocytes (37,38) and central nervous system neurons (39).…”

Section: Discussionmentioning

confidence: 96%

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

Allouche

Bellon

Saidani

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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"Café-au-lait" macules (CALMs) and overall skin hyperpigmentation are early hallmarks of neurofibromatosis type 1 (NF1). One of the most frequent monogenic diseases, NF1 has subsequently been characterized with numerous benign Schwann cell-derived tumors. It is well established that neurofibromin, the NF1 gene product, is an antioncogene that down-regulates the RAS oncogene. In contrast, the molecular mechanisms associated with alteration of skin pigmentation have remained elusive. We have reassessed this issue by differentiating human embryonic stem cells into melanocytes. In the present study, we demonstrate that NF1 melanocytes reproduce the hyperpigmentation phenotype in vitro, and further characterize the link between loss of heterozygosity and the typical CALMs that appear over the general hyperpigmentation. Molecular mechanisms associated with these pathological phenotypes correlate with an increased activity of cAMP-mediated PKA and ERK1/2 signaling pathways, leading to overexpression of the transcription factor MITF and of the melanogenic enzymes tyrosinase and dopachrome tautomerase, all major players in melanogenesis. Finally, the hyperpigmentation phenotype can be rescued using specific inhibitors of these signaling pathways. These results open avenues for deciphering the pathological mechanisms involved in pigmentation diseases, and provide a robust assay for the development of new strategies for treating these diseases.neurofibromatosis type 1 | melanocytes | embryonic stem cells | hyperpigmentation | disease modeling

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Section: Discussionmentioning

confidence: 96%

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

Allouche

Bellon

Saidani

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, the simultaneous activation and intrafamily functional redundancy of Ras proteins in NF1-null MPNST cells suggests that it will be difficult to target these proteins therapeutically. Consequently, some laboratories have asked whether targeting signaling pathways downstream of Ras such as mitogen-activated protein extracellular signal-related kinase (ERK) kinase (MEK) 31,32 and the phosphatidylinositol 3-kinase (PI3K)-Akt-TSC2-mammalian target of rapamycin (mTOR)-S6 kinase 33,34 would be more effective therapeutically. Although initial results indicate that this is the case, note that the full repertoire of Ras-dependent signaling pathways activated in NF1-null peripheral nerve sheath tumors has not yet been defined.…”

Section: Oncogenomics In Mpnst Modelsmentioning

confidence: 99%

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Carroll

2016

The American Journal of Pathology

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Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cellederived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1eassociated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16 INK4A -cyclin D1-CDK4-Rb and p19 ARF -Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. (Am J Pathol 2016, 186: 464e477; http://dx

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“…Fortunately, MEK inhibitors exhibit efficacy in mouse models of clinically important benign tumors associated with neurofibromatosis type 1, including nervous system lesions known as neurofibromas as well as juvenile myelomonocytic leukemia (JMML) (6,7), which has inspired the development of several clinical trials (ClinicalTrials.gov). However, MEK inhibitors are ineffective the most common malignancy associated with neurofibromatosis type 1: malignant peripheral nerve sheath tumors (MPNSTs) (8).…”

Section: Introductionmentioning

confidence: 99%