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Pathology & Oncology Research

, Volume 25, Issue 1, pp 269–278 | Cite as

Clinical Implications of NRAS Overexpression in Resectable Pancreatic Adenocarcinoma Patients

  • Javier Martinez-Useros
  • Weiyao Li
  • Tihomir Georgiev-Hristov
  • Maria J. Fernandez-Aceñero
  • Aurea Borrero-Palacios
  • Nuria Perez
  • Angel Celdran
  • Jesus Garcia-Foncillas
Original Article
  • 92 Downloads

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and its incidence is rising worldwide. Although survival can be improved by surgical resection, when detected at an early stage, this type of cancer is usually asymptomatic, and disease becomes only apparent after metastasis. Adjuvant treatment does not improve survival, thus after surgery there is a lack of predictive and prognosis biomarkers to predict treatment response and survival. The mitogen-activated protein-kinase and phosphoinositide 3-kinase signalling pathways play a crucial role in cancer development and progression. Especially, activated RAS proteins promote cell proliferation through constitutive stimulation of the downstream effectors RAF-MEK-ERK and PI3K-AKT. Mutational status of NRAS is required in several types of cancer like colorectal or cutaneous melanoma. However, mutations in this gene are very scarce in PDAC patients, and NRAS determination is not usually performed in clinical practice for this kind of tumor. In this study, we analyse the association between NRAS protein expression and progression-free survival and overall survival of an homogenous cohort of pancreatic ductal adenocarcinoma patients from a single-centre. Interestingly, we found that patients with high expression not only showed longer progression-free survival than those patients with low expression (22 versus 9 months, respectively) (P = 0.013), but also longer overall survival (43 versus 19 months, respectively) (P = 0.020). These results confirm NRAS expression could be used to differentiate patients according to their prognosis. Proportional hazard model revealed NRAS expression together with grade of differentiation as pathological variables to predict patient’s outcome.

Keywords

Pancreatic ductal adenocarcinoma PDAC NRAS KRAS TGCA Biomarker Progression-free survival Overall survival Grade of differentiation 

Notes

Acknowledgements

We thank Oliver Shaw, PhD (FIIS-FJD) for editing the manuscript for English usage, clarity, and style. We also A. Cazorla MD, PhD for a double-blind tissue immunostainings evaluation and quantification.

Author’s Contribution

J.M.-U. designed the study, analyse data, draft the article and is the guarantor for the article; W.L. and A.B.P. performed experiments; T.G.-H. and M.J.F.-A. performed patients database; N.P., A.C. and J.G.-F. revised critically the manuscript.

Funding

This work has been carried out with Spanish Health Research Project Funds PI16/01468 from “Instituto de Salud Carlos III FEDER” (J.G.-F.), of the Spanish Ministry of Economy, Industry and Competitiveness.

Compliance with Ethical Standards

Conflicts of Interest

None to declare.

Supplementary material

12253_2017_341_MOESM1_ESM.doc (28 kb)
ESM 1 (DOC 28 kb)
12253_2017_341_MOESM2_ESM.doc (28 kb)
ESM 2 (DOC 28 kb)

References

  1. 1.
    Hariharan D, Saied A, Kocher HM (2008) Analysis of mortality rates for pancreatic cancer across the world. HPB 10(1):58–62CrossRefGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30.  https://doi.org/10.3322/caac.21332 CrossRefGoogle Scholar
  3. 3.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90CrossRefGoogle Scholar
  4. 4.
    Egawa S, Takeda K, Fukuyama S, Motoi F, Sunamura M, Matsuno S (2004) Clinicopathological aspects of small pancreatic cancer. Pancreas 28(3):235–240CrossRefGoogle Scholar
  5. 5.
    Ariyama J, Suyama M, Satoh K, Sai J (1998) Imaging of small pancreatic ductal adenocarcinoma. Pancreas 16(3):396–401CrossRefGoogle Scholar
  6. 6.
    Kelsen DP, Portenoy R, Thaler H, Tao Y, Brennan M (1997) Pain as a predictor of outcome in patients with operable pancreatic carcinoma. Surgery 122(1):53–59CrossRefGoogle Scholar
  7. 7.
    Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362(17):1605–1617.  https://doi.org/10.1056/NEJMra0901557 CrossRefGoogle Scholar
  8. 8.
    Stathis A, Moore MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7(3):163–172.  https://doi.org/10.1038/nrclinonc.2009.236 CrossRefGoogle Scholar
  9. 9.
    Fong ZV, Winter JM (2012) Biomarkers in pancreatic cancer: diagnostic, prognostic, and predictive. Cancer J 18(6):530–538.  https://doi.org/10.1097/PPO.0b013e31827654ea CrossRefGoogle Scholar
  10. 10.
    Martinez-Useros J, Garcia-Foncillas J (2016) The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer. Biomed Res Int 2016:1869304.  https://doi.org/10.1155/2016/1869304 Google Scholar
  11. 11.
    Maithel SK, Maloney S, Winston C, Gonen M, D'Angelica MI, Dematteo RP, Jarnagin WR, Brennan MF, Allen PJ (2008) Preoperative CA 19-9 and the yield of staging laparoscopy in patients with radiographically resectable pancreatic adenocarcinoma. Ann Surg Oncol 15(12):3512–3520.  https://doi.org/10.1245/s10434-008-0134-5 CrossRefGoogle Scholar
  12. 12.
    Goonetilleke KS, Siriwardena AK (2007) Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 33(3):266–270.  https://doi.org/10.1016/j.ejso.2006.10.004 CrossRefGoogle Scholar
  13. 13.
    Bosman FTCF, Hruban RH, Theise ND (eds) (2010) World Health Organization Classification of Tumours of the Digestive System. IARC Press, LyonGoogle Scholar
  14. 14.
    Klöppel GHR, Longnecker DS, Adler G, Kern SE, Partanen TJ (2000) Ductal adenocarcinoma of the pancreas. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. IARC Press, LyonGoogle Scholar
  15. 15.
    Kim JE, Lee KT, Lee JK, Paik SW, Rhee JC, Choi KW (2004) Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population. J Gastroenterol Hepatol 19(2):182–186CrossRefGoogle Scholar
  16. 16.
    Kawai S, Suzuki K, Nishio K, Ishida Y, Okada R, Goto Y, Naito M, Wakai K, Ito Y, Hamajima N (2008) Smoking and serum CA19-9 levels according to Lewis and secretor genotypes. Int J Cancer 123(12):2880–2884.  https://doi.org/10.1002/ijc.23907 CrossRefGoogle Scholar
  17. 17.
    Burotto M, Chiou VL, Lee JM, Kohn EC (2014) The MAPK pathway across different malignancies: a new perspective. Cancer 120(22):3446–3456.  https://doi.org/10.1002/cncr.28864 CrossRefGoogle Scholar
  18. 18.
    Kolch W (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6(11):827–837.  https://doi.org/10.1038/nrm1743 CrossRefGoogle Scholar
  19. 19.
    Colicelli J (2004) Human RAS superfamily proteins and related GTPases. Sci STKE 2004(250):RE13.  https://doi.org/10.1126/stke.2502004re13 Google Scholar
  20. 20.
    Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3(6):459–465.  https://doi.org/10.1038/nrc1097 CrossRefGoogle Scholar
  21. 21.
    Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26(22):3291–3310.  https://doi.org/10.1038/sj.onc.1210422 CrossRefGoogle Scholar
  22. 22.
    Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V, Massi D, Fonsatti E, Staibano S, Nappi O, Pagani E, Casula M, Manca A, Sini M, Franco R, Botti G, Caraco C, Mozzillo N, Ascierto PA, Palmieri G (2012) BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol 30(20):2522–2529.  https://doi.org/10.1200/JCO.2011.41.2452 CrossRefGoogle Scholar
  23. 23.
    Edlundh-Rose E, Egyhazi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, Lundeberg J (2006) NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 16(6):471–478.  https://doi.org/10.1097/01.cmr.0000232300.22032.86 CrossRefGoogle Scholar
  24. 24.
    Seo JS, Ju YS, Lee WC, Shin JY, Lee JK, Bleazard T, Lee J, Jung YJ, Kim JO, Yu SB, Kim J, Lee ER, Kang CH, Park IK, Rhee H, Lee SH, Kim JI, Kang JH, Kim YT (2012) The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22(11):2109–2119.  https://doi.org/10.1101/gr.145144.112 CrossRefGoogle Scholar
  25. 25.
    Bansal M, Gandhi M, Ferris RL, Nikiforova MN, Yip L, Carty SE, Nikiforov YE (2013) Molecular and histopathologic characteristics of multifocal papillary thyroid carcinoma. Am J Surg Pathol 37(10):1586–1591.  https://doi.org/10.1097/PAS.0b013e318292b780 CrossRefGoogle Scholar
  26. 26.
    Cancer_Genome_Atlas_Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337.  https://doi.org/10.1038/nature11252 CrossRefGoogle Scholar
  27. 27.
    Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995.  https://doi.org/10.1158/0008-5472.CAN-06-0191 CrossRefGoogle Scholar
  28. 28.
    Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL (1988) KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res 16(16):7773–7782CrossRefGoogle Scholar
  29. 29.
    Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, Hruban RH, Maitra A, Kinzler K, Vogelstein B, Goggins M (2012) Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142(4):730–733 e739.  https://doi.org/10.1053/j.gastro.2011.12.042 CrossRefGoogle Scholar
  30. 30.
    Mitsuhashi K, Nosho K, Sukawa Y, Matsunaga Y, Ito M, Kurihara H, Kanno S, Igarashi H, Naito T, Adachi Y, Tachibana M, Tanuma T, Maguchi H, Shinohara T, Hasegawa T, Imamura M, Kimura Y, Hirata K, Maruyama R, Suzuki H, Imai K, Yamamoto H, Shinomura Y (2015) Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget 6(9):7209–7220.  10.18632/oncotarget.3109 CrossRefGoogle Scholar
  31. 31.
    Hamidi H, Lu M, Chau K, Anderson L, Fejzo M, Ginther C, Linnartz R, Zubel A, Slamon DJ, Finn RS (2014) KRAS mutational subtype and copy number predict in vitro response of human pancreatic cancer cell lines to MEK inhibition. Br J Cancer 111(9):1788–1801.  https://doi.org/10.1038/bjc.2014.475 CrossRefGoogle Scholar
  32. 32.
    Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491(7424):399–405.  https://doi.org/10.1038/nature11547 CrossRefGoogle Scholar
  33. 33.
    Deschenes-Simard X, Gaumont-Leclerc MF, Bourdeau V, Lessard F, Moiseeva O, Forest V, Igelmann S, Mallette FA, Saba-El-Leil MK, Meloche S, Saad F, Mes-Masson AM, Ferbeyre G (2013) Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev 27(8):900–915.  https://doi.org/10.1101/gad.203984.112 CrossRefGoogle Scholar
  34. 34.
    Serrano M, Lin AW, ME MC, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88(5):593–602CrossRefGoogle Scholar
  35. 35.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1.  https://doi.org/10.1126/scisignal.2004088 CrossRefGoogle Scholar
  36. 36.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404.  https://doi.org/10.1158/2159-8290.CD-12-0095 CrossRefGoogle Scholar
  37. 37.
    Li B, Ruotti V, Stewart RM, Thomson JA, Dewey CN (2010) RNA-Seq gene expression estimation with read mapping uncertainty. Bioinformatics 26(4):493–500.  https://doi.org/10.1093/bioinformatics/btp692 CrossRefGoogle Scholar
  38. 38.
    Adsay NV, Basturk O, Bonnett M, Kilinc N, Andea AA, Feng J, Che M, Aulicino MR, Levi E, Cheng JD (2005) A proposal for a new and more practical grading scheme for pancreatic ductal adenocarcinoma. Am J Surg Pathol 29(6):724–733CrossRefGoogle Scholar
  39. 39.
    Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW (2004) Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 91(5):586–594.  https://doi.org/10.1002/bjs.4484 CrossRefGoogle Scholar
  40. 40.
    Cucchetti A, Ercolani G, Taffurelli G, Serenari M, Maroni L, Pezzilli R, Del Gaudio M, Ravaioli M, Cescon M, Pinna AD (2016) A comprehensive analysis on expected years of life lost due to pancreatic cancer. Pancreatology 16(3):449–453CrossRefGoogle Scholar
  41. 41.
    Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goere D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T, Arnold D (2015) Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 56:v56–v68CrossRefGoogle Scholar
  42. 42.
    Tempero MA MM, Al-Hawary M, Behrman SW, Benson A1, Berlin JD, Cha C, Chiorean EG, Chung V, Cohen SJ, Czito B, Dillhoff M, Feng M, Ferrone CR, Hardacre J, Hawkins W, Herman J, Hoffman JP, Ko AH, Komanduri S, Koong A, Lowy AM, Ma WW, Moravek C, Mulvihill SJ, Nakakura EK, O’Reilly EM, Obando J, Reddy S, Thayer S, Weekes CD, Wolff RA, Wolpin BM, Burns J, Darlow S (2016) Pancreatic Adenocarcinoma Version 1.2016. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) National Comprehensive Cancer NetworkGoogle Scholar
  43. 43.
    Abbruzzese JL (2002) New applications of gemcitabine and future directions in the management of pancreatic cancer. Cancer 95(4 Suppl):941–945.  https://doi.org/10.1002/cncr.10753 CrossRefGoogle Scholar
  44. 44.
    Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363(9414):1049–1057.  https://doi.org/10.1016/S0140-6736(04)15841-8 CrossRefGoogle Scholar
  45. 45.
    Winter JM, Yeo CJ, Brody JR (2013) Diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. J Surg Oncol 107(1):15–22CrossRefGoogle Scholar
  46. 46.
    Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, Farrugia DJ, Couch FJ, Urban N, Taniguchi T (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451(7182):1116–1120CrossRefGoogle Scholar
  47. 47.
    Kakavand H, Walker E, Lum T, Wilmott JS, Selinger CI, Smith E, Saw RP, Yu B, Cooper WA, Long GV, O'Toole SA, Scolyer RA (2016) BRAF(V600E) and NRAS(Q61L/Q61R) mutation analysis in metastatic melanoma using immunohistochemistry: a study of 754 cases highlighting potential pitfalls and guidelines for interpretation and reporting. Histopathology 69(4):680–686.  https://doi.org/10.1111/his.12992 CrossRefGoogle Scholar
  48. 48.
    Martinez-Useros J, Georgiev-Hristov T, Fernandez-Acenero MJ, Borrero-Palacios A, Indacochea A, Guerrero S, Li W, Cebrian A, Gomez Del Pulgar T, Puime-Otin A, Del Puerto-Nevado L, Rodriguez-Remirez M, Perez N, Celdran A, Gebauer F, Garcia-Foncillas J (2017) UNR/CDSE1 expression as prognosis biomarker in resectable pancreatic ductal adenocarcinoma patients: A proof-of-concept. PLoS One 12(8):e0182044.  https://doi.org/10.1371/journal.pone.0182044 CrossRefGoogle Scholar
  49. 49.
    De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762.  https://doi.org/10.1016/S1470-2045(10)70130-3 CrossRefGoogle Scholar
  50. 50.
    Palomba G, Doneddu V, Cossu A, Paliogiannis P, Manca A, Casula M, Colombino M, Lanzillo A, Defraia E, Pazzola A, Sanna G, Putzu C, Ortu S, Scartozzi M, Ionta MT, Baldino G, Sarobba G, Capelli F, Sedda T, Virdis L, Barca M, Gramignano G, Budroni M, Tanda F, Palmieri G (2016) Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study. J Transl Med 14(1):292.  https://doi.org/10.1186/s12967-016-1053-z CrossRefGoogle Scholar
  51. 51.
    Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263.  https://doi.org/10.1016/j.cell.2012.06.024 CrossRefGoogle Scholar
  52. 52.
    Prior IA, Lewis PD, Mattos C (2012) A comprehensive survey of Ras mutations in cancer. Cancer Res 72(10):2457–2467.  https://doi.org/10.1158/0008-5472.CAN-11-2612 CrossRefGoogle Scholar
  53. 53.
    Fiore D, Donnarumma E, Roscigno G, Iaboni M, Russo V, Affinito A, Adamo A, De Martino F, Quintavalle C, Romano G, Greco A, Soini Y, Brunetti A, Croce CM, Condorelli G (2016) miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through down-regulation of NRAS. Oncotarget 7(15):19531–19547.  10.18632/oncotarget.6968 CrossRefGoogle Scholar
  54. 54.
    Wang L, Shi ZM, Jiang CF, Liu X, Chen QD, Qian X, Li DM, Ge X, Wang XF, Liu LZ, You YP, Liu N, Jiang BH (2014) MiR-143 acts as a tumor suppressor by targeting N-RAS and enhances temozolomide-induced apoptosis in glioma. Oncotarget 5(14):5416–5427.  10.18632/oncotarget.2116 Google Scholar
  55. 55.
    Lidsky M, Antoun G, Speicher P, Adams B, Turley R, Augustine C, Tyler D, Ali-Osman F (2014) Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells. J Biol Chem 289(40):27714–27726.  https://doi.org/10.1074/jbc.M113.532432 CrossRefGoogle Scholar
  56. 56.
    Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468(7326):973–977.  https://doi.org/10.1038/nature09626 CrossRefGoogle Scholar
  57. 57.
    Birkeland E, Busch C, Berge EO, Geisler J, Jonsson G, Lillehaug JR, Knappskog S, Lonning PE (2013) Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma. Clin Exp Metastasis 30(7):867–876.  https://doi.org/10.1007/s10585-013-9587-4 CrossRefGoogle Scholar
  58. 58.
    Eisfeld AK, Schwind S, Hoag KW, Walker CJ, Liyanarachchi S, Patel R, Huang X, Markowitz J, Duan W, Otterson GA, Carson WE 3rd, Marcucci G, Bloomfield CD, de la Chapelle A (2014) NRAS isoforms differentially affect downstream pathways, cell growth, and cell transformation. Proc Natl Acad Sci U S A 111(11):4179–4184.  https://doi.org/10.1073/pnas.1401727111 CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  • Javier Martinez-Useros
    • 1
  • Weiyao Li
    • 1
  • Tihomir Georgiev-Hristov
    • 2
  • Maria J. Fernandez-Aceñero
    • 3
  • Aurea Borrero-Palacios
    • 1
  • Nuria Perez
    • 4
  • Angel Celdran
    • 2
  • Jesus Garcia-Foncillas
    • 1
  1. 1.Translational Oncology Division, OncoHealth InstituteFundacion Jimenez Diaz University Hospital, Autonomous University of MadridMadridSpain
  2. 2.Hepatobiliary and Pancreatic Surgery Unit, General and Digestive Tract Surgery DepartmentFundacion Jimenez Diaz University HospitalMadridSpain
  3. 3.Department of PathologyClinico San Carlos University HospitalMadridSpain
  4. 4.Department of PathologyUniversity Hospital Fundacion Jimenez DiazMadridSpain

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