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Cited by 258Melanoma and MAPK PathwaysNeurofibromatosis and Schwannoma CasesCutaneous Melanoma Detection and Management

Elucidating Distinct Roles for NF1 in Melanomagenesis

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Maertens, Ophélia, Johnson, Bryan, Hollstein, Pablo, Frederick, Dennie T., Cooper, Zachary A., Messiaen, Ludwine, Bronson, Roderick T., McMahon, Martin +5 more·2013·Cancer Discovery
DOI 10.1158/2159-8290.cd-12-0313PMC PMC3595355

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Abstract

BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal–regulated kinase pathways. As such, Nf1/Braf–mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal–regulated kinase kinase and mTOR. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and show that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies. Significance: This study elucidates the mechanism by which NF1 mutations cooperate with different BRAF mutations in melanomagenesis and shows that NF1/neurofibromin loss may desensitize tumors to BRAF inhibitors. Cancer Discov; 3(3); 338–49. ©2012 AACR. See related commentary by Gibney and Smalley, p. 260 This article is highlighted in the In This Issue feature, p. 239

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  • The APOE variants exert cell-intrinsic effects on melanoma that impact primary tumor growth and metastatic capacity in a BrafV600E-driven GEMM.

    “We reveal that the APOE variants exert cell-intrinsic effects on melanoma that impact primary tumor growth and metastatic capacity in a BrafV600E-driven GEMM, a model that has provided numerous important insights into melanoma biology (12,38–40).”

    From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [39]

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References 59 · Cited by 258

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  1. [2]Kuilman T Michaloglou C Mooi WJ Peeper DS The essence of senescence Genes Dev 2010 24 2463 2479 21078816 PMC2975923
  2. [3]Bartkova J Rezaei N Liontos M Karakaidos P Kletsas D Issaeva N Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints Nature 2006 444 633 637 17136093
  3. [4]Di Micco R Fumagalli M Cicalese A Piccinin S Gasparini P Luise C Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication Nature 2006 444 638 642 17136094
  4. [11]Gray-Schopfer VC Cheong SC Chong H Chow J Moss T Abdel-Malek ZA Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 2006 95 496 505 16880792 PMC2360676
  5. [12]Michaloglou C Vredeveld LC Soengas MS Denoyelle C Kuilman T van der Horst CM BRAFE600-associated senescence-like cell cycle arrest of human naevi Nature 2005 436 720 724 16079850
  6. [13]Garnett MJ Marais R Guilty as charged: B-RAF is a human oncogene Cancer Cell 2004 6 313 319 15488754
  7. [14]Dankort D Curley DP Cartlidge RA Nelson B Karnezis AN Damsky WE Jr Braf(V600E) cooperates with Pten loss to induce metastatic melanoma Nat Genet 2009 41 544 552 19282848 PMC2705918
  8. [15]Dhomen N Reis-Filho JS da Rocha Dias S Hayward R Savage K Delmas V Oncogenic Braf induces melanocyte senescence and melanoma in mice Cancer Cell 2009 15 294 303 19345328
  9. [16]Pollock PM Harper UL Hansen KS Yudt LM Stark M Robbins CM High frequency of BRAF mutations in nevi Nat Genet 2003 33 19 20 12447372
  10. [17]Vredeveld LC Possik PA Smit MA Meissl K Michaloglou C Horlings HM Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis Genes Dev 2012 26 1055 1069 22549727 PMC3360561
  11. [18]Bernards A Settleman J GAPs in growth factor signalling Growth Factors 2005 23 143 149 16019436
  12. [19]Dasgupta B Yi Y Chen DY Weber JD Gutmann DH Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors Cancer Res 2005 65 2755 2760 15805275
  13. [20]Johannessen CM Reczek EE James MF Brems H Legius E Cichowski K The NF1 tumor suppressor critically regulates TSC2 and mTOR Proc Natl Acad Sci U S A 2005 102 8573 8578 15937108 PMC1142482
  14. [21]Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 2008 455 1061 1068 18772890 PMC2671642
  15. [23]McGillicuddy LT Fromm JA Hollstein PE Kubek S Beroukhim R De Raedt T Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis Cancer Cell 2009 16 44 54 19573811 PMC2897249
  16. [25]Holzel M Huang S Koster J Ora I Lakeman A Caron H NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome Cell 2010 142 218 229 20655465 PMC2913027
  17. [26]Bosch E Cherwinski H Peterson D McMahon M Mutations of critical amino acids affect the biological and biochemical properties of oncogenic A-Raf and Raf-1 Oncogene 1997 15 1021 1033 9285556
  18. [27]Zhu J Woods D McMahon M Bishop JM Senescence of human fibroblasts induced by oncogenic Raf Genes Dev 1998 12 2997 3007 9765202 PMC317194
  19. [28]Woods D Parry D Cherwinski H Bosch E Lees E McMahon M Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1 Mol Cell Biol 1997 17 5598 5611 9271435 PMC232408
  20. [29]De Schepper S Boucneau J Lambert J Messiaen L Naeyaert JM Pigment cell-related manifestations in neurofibromatosis type 1: an overview Pigment Cell Res 2005 18 13 24 15649148
  21. [30]Zhu Y Romero MI Ghosh P Ye Z Charnay P Rushing EJ Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain Genes Dev 2001 15 859 876 11297510 PMC312666
  22. [31]Dankort D Filenova E Collado M Serrano M Jones K McMahon M A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors Genes Dev 2007 21 379 384 17299132 PMC1804325
  23. [32]Bosenberg M Muthusamy V Curley DP Wang Z Hobbs C Nelson B Characterization of melanocyte-specific inducible Cre recombinase transgenic mice Genesis 2006 44 262 267 16676322
  24. [33]Ramjaun AR Downward J Ras and phosphoinositide 3-kinase: partners in development and tumorigenesis Cell Cycle 2007 6 2902 2905 17993782
  25. [34]Johannessen CM Johnson BW Williams SM Chan AW Reczek EE Lynch RC TORC1 is essential for NF1-associated malignancies Curr Biol 2008 18 56 62 18164202
  26. [35]Ji Z Flaherty KT Tsao H Targeting the RAS pathway in melanoma Trends Mol Med 2012 18 27 35 21962474 PMC3759017
  27. [36]Bollag G Hirth P Tsai J Zhang J Ibrahim PN Cho H Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma Nature 2010 467 596 599 20823850 PMC2948082
  28. [38]Heidorn SJ Milagre C Whittaker S Nourry A Niculescu-Duvas I Dhomen N Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF Cell 2010 140 209 221 20141835 PMC2872605
  29. [39]Lin WM Baker AC Beroukhim R Winckler W Feng W Marmion JM Modeling genomic diversity and tumor dependency in malignant melanoma Cancer Res 2008 68 664 673 18245465 PMC10493008
  30. [40]Smalley KS Xiao M Villanueva J Nguyen TK Flaherty KT Letrero R CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations Oncogene 2009 28 85 94 18794803 PMC2898184
  31. [41]Guldberg P thor Straten P Birck A Ahrenkiel V Kirkin AF Zeuthen J Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma Cancer Res 1997 57 3660 3663 9288767
  32. [43]Nazarian R Shi H Wang Q Kong X Koya RC Lee H Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation Nature 2010 468 973 977 21107323 PMC3143360
  33. [44]Poulikakos PI Persaud Y Janakiraman M Kong X Ng C Moriceau G RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) Nature 2011 480 387 390 22113612 PMC3266695
  34. [45]Shi H Moriceau G Kong X Lee MK Lee H Koya RC Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance Nat Commun 2012 3 724 22395615 PMC3530385
  35. [46]Villanueva J Vultur A Lee JT Somasundaram R Fukunaga-Kalabis M Cipolla AK Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K Cancer Cell 2010 18 683 695 21156289 PMC3026446
  36. [47]Paraiso KH Xiang Y Rebecca VW Abel EV Chen YA Munko AC PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression Cancer Res 2011 71 2750 2760 21317224 PMC3070772
  37. [48]Shao Y Aplin AE Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells Cancer Res 2010 70 6670 6681 20647317 PMC2922482
  38. [49]Cichowski K Santiago S Jardim M Johnson BW Jacks T Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor Genes Dev 2003 17 449 454 12600938 PMC195996
  39. [50]Dimri GP Lee X Basile G Acosta M Scott G Roskelley C A biomarker that identifies senescent human cells in culture and in aging skin in vivo Proc Natl Acad Sci U S A 1995 92 9363 9367 7568133 PMC40985
  40. [51]Messiaen LM Callens T Mortier G Beysen D Vandenbroucke I Van Roy N Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects Hum Mutat 2000 15 541 555 10862084
  41. [52]Wimmer K Yao S Claes K Kehrer-Sawatzki H Tinschert S De Raedt T Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients Genes Chromosomes Cancer 2006 45 265 276 16283621
  42. [54]Forbes SA Bindal N Bamford S Cole C Kok CY Beare D COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer Nucleic Acids Res 2011 39 D945 D950 20952405 PMC3013785
  43. [55]Berger MF Hodis E Heffernan TP Deribe YL Lawrence MS Protopopov A Melanoma genome sequencing reveals frequent PREX2 mutations Nature 2012 485 502 506 22622578 PMC3367798
  44. [57]Krauthammer M Kong Y Ha BH Evans P Bacchiocchi A McCusker JP Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma Nat Genet 2012 44 1006 1014 22842228 PMC3432702

Authors
Maertens, O., Johnson, B., Hollstein, P., Frederick, D. T., Cooper, Z. A., Messiaen, L., Bronson, R. T., McMahon, M., Granter, S., Flaherty, K., Wargo, J. A., Marais, R., & Cichowski, K.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
Cichowski, Karen
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2013-03-01
Volume
3
Issue
3
Pages
338-349
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-12-0313
PMC
PMC3595355
OpenAlex
W2133403796
Cited by
258
References
59
Citations by year
2026: 10 · 2025: 7 · 2024: 14 · 2023: 9 · 2022: 16 · 2021: 28 · 2020: 21 · 2019: 13 · 2018: 24 · 2017: 25 · 2016: 18 · 2015: 24 · 2014: 32 · 2013: 15 · 2012: 1
FWCI
9.26
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • European Association for Cancer Research
  • Cancer Research UK (17240, 19279)
  • Fonds Wetenschappelijk Onderzoek
  • Servier
  • National Cancer Institute (R01CA129814, R01CA176839, R01CA111754, P30CA006516)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
Keywords
neurofibromatosis type 1, neurofibromin, melanomagenesis, BRAF mutation, oncogene-induced senescence, melanoma, phosphatidylinositol 3-kinase, ERK signaling, mTOR, BRAF inhibitors, drug resistance, combination therapy, genetically engineered mouse models
MeSH terms
Vemurafenib, Animals, Disease Models, Animal, Genotype, Humans, Indoles, Melanocytes, Melanoma, Mice, Nude, Mutation, Sulfonamides, Signal Transduction, Genes, Neurofibromatosis 1, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Neurofibromin 1, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Growth Processes, Mice, Carcinogenesis

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