Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice

Chang, Tiffany; Krisman, Kimberly; Theobald, Emily Harding; Xu, Jin; Akutagawa, Jon; Lauchle, Jennifer; Kogan, Scott C.; Braun, Benjamin S.; Shannon, Kevin

doi:10.1172/jci63193

Cited by 113 publications

(65 citation statements)

References 17 publications

(27 reference statements)

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“…Consistent with a major role for RAS–MAPK signalling in JMML, preclinical testing showed significant response to inhibition of MEK 151 . Disease burden was markedly reduced, although mutant stem cells persisted.…”

Section: Therapeutic Implicationsmentioning

confidence: 56%

“…10) and a RAS-driven haematopoietic stem cell disorder. Thus, patients with NF1 and patients with RASopathies who have mutations in NRAS , KRAS , CBL , protein tyrosine phosphatase non-receptor type 11 ( PTPN11 ; also known as SHP2 ) or son of sevenless homologue 1 ( SOS1 ) are predisposed to this low-grade leukaemia 150 , which is recapitulated in an Mx1 – Cre;Nf1 fl/fl model 151 .…”

Section: Nf1 Tumorigenesis and Tumour Cells Of Originmentioning

confidence: 99%

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A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

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Section: Therapeutic Implicationsmentioning

confidence: 56%

Section: Nf1 Tumorigenesis and Tumour Cells Of Originmentioning

confidence: 99%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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“…This has prompted the use of specific MAP Kinase pathway inhibitors to counteract Nf1 loss-mediated tumor development (Chang et al, 2013; Jessen et al, 2013; Staser et al, 2013) or to treat Nf1 mutant animals in the effort to restore abnormal brain development and cognitive function (Li et al, 2012; Lush et al, 2008; Wang et al, 2012). To determine if our non-germ line plexiform neurofibroma model could be used as a rapid preclinical therapeutic drug screening tool to indentify effective therapies, we used a highly selective pharmacological inhibitor of MEK, PD0325901 that blocks activation and phosphorylation of ERK1/2 (Chang et al, 2013) to test whether inhibition of the Ras/Raf/MEK/ERK signaling pathway can prevent neurofibroma progression in our plexiform neurofibroma model.…”

Section: Resultsmentioning

confidence: 99%

Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

et al. 2014

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Summary Neurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell-type that gives rise to neurofibromas. Using cell-lineage tracing, we identify a population of GAP43+ PLP+ precursors in embryonic nerve roots as the cells of origin for these tumors and report a non-germline model of neurofibroma for preclinical drug screening to identify effective therapies. The identity of tumor cell-of-origin and facility for isolation and expansion provides fertile ground for continued analysis to define intrinsic and extrinsic factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients.

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“…First, the use of these GEM strains has revealed that the precise mechanism by which neurofibromin (or merlin) regulates cell growth or function varies from tissue to tissue. For example, neurofibromin growth regulation in NF1 -deficient leukemic cells is primarily related to increased RAS/MEK signaling [56,57], whereas in Nf1 -deficient astrocytes, neurofibromin growth control reflects RAS/mTOR hyperactivation [58,59]. Additionally, in some NF1-associated tumors (plexiform neurofibromas), both Ras/MEK and Ras/mTOR hyperactivation underlie increased proliferation [56,57,60].…”

Section: Molecular Targets For Therapeutic Trialsmentioning

confidence: 99%

“…For example, neurofibromin growth regulation in NF1 -deficient leukemic cells is primarily related to increased RAS/MEK signaling [56,57], whereas in Nf1 -deficient astrocytes, neurofibromin growth control reflects RAS/mTOR hyperactivation [58,59]. Additionally, in some NF1-associated tumors (plexiform neurofibromas), both Ras/MEK and Ras/mTOR hyperactivation underlie increased proliferation [56,57,60]. Similarly, Nf2 -deficient glial cells depend on merlin inhibition of ErbB2 activation [54], while other Nf2 -deficient cell types are dependent on merlin suppression of a related RTK, the EGFR [55].…”

Section: Molecular Targets For Therapeutic Trialsmentioning

confidence: 99%

Optimizing biologically targeted clinical trials for neurofibromatosis

Gutmann

Blakeley²,

Korf

et al. 2013

Expert Opinion on Investigational Drugs

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Introduction The neurofibromatoses (neurofibromatosis type 1, NF1 and neurofibromatosis type 2, NF2) comprise the most common inherited conditions in which affected children and adults develop tumors of the central and peripheral nervous system. In this review, the authors discuss how the establishment of the Neurofibromatosis Clinical Trials Consortium (NFCTC) has positively impacted on the design and execution of treatment studies for individuals with NF1 and NF2. Areas covered Using an extensive PUBMED search in collaboration with select NFCTC members expert in distinct NF topics, the authors discuss the clinical features of NF1 and NF2, the molecular biology of the NF1 and NF2 genes, the development and application of clinically relevant Nf1 and Nf2 genetically engineered mouse models and the formation of the NFCTC to enable efficient clinical trial design and execution. Expert opinion The NFCTC has resulted in a more seamless integration of mouse preclinical and human clinical trials efforts. Leveraging emerging enabling resources, current research is focused on identifying subtypes of tumors in NF1 and NF2 to deliver the most active compounds to the patients most likely to respond to the targeted therapy.

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Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice

Cited by 113 publications

References 17 publications

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

Optimizing biologically targeted clinical trials for neurofibromatosis

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