Mariano Barbacid Group Leader
T +34 912246933 (Ext 4000)
mbarbacid@cnio.es

KRAS oncogenes have been implicated in one fifth of all human tumours including lung and pancreatic adenocarcinomas, two tumour types with some of the worse prognosis. Unfortunately, identification of suitable therapies to treat these tumours remains elusive and patients are still treated with cytotoxic compounds approved over 2 decades ago. The recent discovery that tumours display intra-tumour heterogeneity adds another layer of complexity that needs to be addressed. Hence, we have decided to search for novel therapeutic targets that contribute to the early stages of tumour development, arguing that they should be present in all tumour cells and not only in evolving clones. In addition, we have continued our quest to validate known targets among the members of the MAPK and PI3K pathways using genetically engineered mouse tumour models with the ultimate goal of establishing rational combination therapies that may provide significant therapeutic benefits in the clinic.

Publications

• PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling(2019)
  Z. Yao, Y. Gao, W. Su1, R. Yaeger, J. Tao, N. Na, Y. Zhang, C. Zhang, A. Rymar, A. Tao, N.M.Timaul, R. Mcgriskin, N.A. Outmezguine, H.Y. Zhao, Q. Chang , B. Qeriqi, M. Barbacid, E. de Stanchina, D.M. Hyman, G. Bollag and N. Rosen.
  Nat Med 25, 284-291.
• c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling(2018)
  Sanclemente M, Francoz S, Esteban-Burgos L, Bousquet-Mur E, Djurec M, Lopez-Casas PP, Hidalgo M, Guerra C, Drosten M, Musteanu M, Barbacid M
  Cancer Cell 33, 217-228.
• Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors.(2018)
  Djurec M, Graña O, Lee A, Troulé K, Espinet E, Cabras L, Navas C, Blasco MT, Martín-Díaz L, Burdiel M, Li J, Liu Z, Vallespinós M, Sanchez-Bueno F, Sprick MR, Trumpp A, Sainz B Jr., Al-Shahrour F, Rabadan R, Guerra C, Barbacid M.
  Proc Natl Acad Sci USA 115, E1147-E1156.
• Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma.(2018)
  Sonntag R, Giebeler N, Nevzorova YA, Bangen JM, Fahrenkamp D, Lambertz D, Haas U, Hu W, Gassler N, Cubero FJ, Müller-Newen G, Abdallah AT, Weiskirchen R, Ticconi F, Costa IG, Barbacid M, Trautwein C, Liedtke C.
  Proc Natl Acad Sci USA (in press).
• Genetically Engineered Mouse Models of K-Ras-Driven Lung and Pancreatic Tumors: Validation of Therapeutic Targets.(2018)
  Drosten M, Guerra C, Barbacid M.
  Cold Spring Harb Perspect Med 8, a031542-.
• Effects of a Ketogenic Diet on [18F]FDG-PET Imaging in a Mouse Model of Lung Cancer.(2018)
  Cussó L, Musteanu M, Mulero F, Barbacid M, Desco M.
  Mol Imaging Biol (in press).
• The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer.(2018)
  Simón-Carrasco L, Jiménez G, Barbacid M, Drosten M.
  Cell Cycle 17, 702-711.
• ERF deletion rescues RAS deficiency in mouse embryonic stem cells.(2018)
  Mayor-Ruiz C, Olbrich T, Drosten M, Lecona E, Vega-Sendino M, Ortega S, Dominguez O, Barbacid M, Ruiz S, Fernandez-Capetillo O.
  Genes Dev 32, 568-576.
• Allele-specific mechanisms of activation of MEK1 mutants determine their properties.(2018)
  Y. Gao, M. Chang, D. McKay, N. Na, B. Zhou, R. Yaeger, N. Torres, K. Muniz, M. Drosten, M. Barbacid, G. Caponigro, D. Stuart, H. Möbitz, D. Solit, O. Abdel-Wahab, B. Taylor, Z. Yao, and N. Rosen.
  Cancer Discovery 8, 648-651.
• Afatinib restrains K-RAS driven lung tumorigenesis(2018)
  H.P. Moll, K. Pranz, M. Musteanu3, B. Grabner2, N. Hruschka2, J. Mohrherr2, P. Aigner, P. Stiedl, L. Brcic, V. Laszlo, D. Schramek, R. Moriggl, R. Eferl, J. Moldvay, K. Dezso, P. P. Lopez-Casas3, D. Stoiber, M. Hidalgo, J. Penninger, M. Sibilia, B. Gy?rffy, M. Barbacid, B. Dome, H. Popper, E. Casanova.
  Sci Transl Med 10, 446-.
• Targeting galectin-1 inhibits pancreatic cancer progression by interrupting tumor-stroma cross-talk.(2018)
  Orozco CA, Martinez-Bosch N, Guerrero PE, Vinaixa J, Iglesias M, Moreno M, Djurec M, Poirier F, Gabius HJ, Fernandez-Zapico M, Hwang RF, Guerra C, Rabinovich G and Navarro P.
  Proc Natl Acad Sci USA 115, E3769-E3778.
• A Braf kinase-inactive mutant induces lung adenocarcinoma.(2017)
  Nieto P, Ambrogio C, Esteban-Burgos L, Gómez-López G, Blasco MT, Yao Z, Marais R, Rosen N, Chiarle R, Pisano DG, Barbacid M and Santamaría D
  Nature 548, 239-243.
• Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.(2017)
  Yao Z, Yaeger R, Tao A, Torres NM, Chang MT, Drosten M, Zhao H, Rodrik-Outmezguine VS, Cecchi F, Hembrough T, Michels J, Baumert H, Miles L, Campbell NM, de Stanchina E, Solit DB, Barbacid M, Taylor BS and Rosen N
  Nature 548, 234-238.
• Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.(2017)
  Papale A, d'Isa R, Menna E, Cerovic M, Solari N, Hardingham N, Cambiaghi M, Cursi M, Barbacid M, Leocani L, Fasano S, Matteoli M, Brambilla R
  Biol Psychiat 81, 179-192.
• Inactivation of Capicua in adult mice causes T cell lymphoblastic lymphoma.(2017)
  Simón-Carrasco L, Graña O, Salmón M, Jacob HKC, Gutierrez A, Jiménez G, Drosten M, Barbacid M
  Genes Dev 31, 1456-1468.
• H-Ras and K-Ras oncoproteins induce different tumor spectra when driven by the same regulatory sequences.(2017)
  Drosten M, Simón-Carrasco L, Hernández-Porras I, Lechuga CG, Blasco MT, Jacob HK, Fabbiano S, Potenza N, Bustelo XR, Guerra C, Barbacid M
  Cancer Res 77, 707-718.
• A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer.(2017)
  Forés M, Simón-Carrasco L, Ajuria L, Samper N, González-Crespo S, Drosten M, Barbacid M, Jiménez G
  PLoS Genet 13, e1006622-.
• In vivo oncogenic conflicto triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma.(2017)
  Ambrogio C, Barbacid M, Santamaría D
  Oncogene 36, 2309-2318.
• Cdk4 regulates adult neural stem cell proliferation and differentiation in response to insulin-IRS2 signals.(2017)
  Chirivella L, Kirstein M, Ferrón SR, Domingo-Muelas A, Durupt FC, Acosta-Umanzor C, Cano-Jaimez M, Pérez-Sánchez F, Barbacid M, Ortega S, Burks D, Fariñas I
  Stem Cells 35, 2403-2416.
• Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models.(2017)
  Schreiber J, Grimbergen LA, Overwater I, Vaart TV, Stedehouder J, Schuhmacher AJ, Guerra C, Kushner SA, Jaarsma D, Elgersma Y
  Sci Rep 7, 1256-.
• Genetically engineered mouse models of K-Ras driven lung and pancreatic tumors: Validation of therapeutic targets. In Additional Perspectives on Ras and Cancer in the 21st Century (ed. L. VanAelst, J. Downward and F. McCormick).(2017)
  Drosten M, Guerra C and Barbacid M
  Cold Spring Harbor Laboratory Press (in press).
• Modeling Rasopathies with genetically modified mouse models.(2017)
  Hernández-Porras I, Guerra C
  Methods Mol Biol 1487, 379-408.
• The European Cancer Patient’s Bill of Rights, update and implementation 2016.(2017)
  Højgaard L, Löwenberg B, Selby P, Lawler M, Banks I, Law K, Albreht T, Armand JP, Barbacid M, Barzach M, Bergh J, Cameron D, Conte P, de Braud F, de Gramont A, De Lorenzo F, Diehl V, Diler S, Erdem S, Geissler J, Gore-Booth J, Henning G, Horgan D, Jassem J, Johnson P, Kaasa S, Kapitein P, Karjalainen S, Kelly J, Kienesberger A, La Vecchia C, Lacombe D, Lindahl T, Luzzatto L, Malby R, Mastris K, Meunier F, Murphy M, Naredi P, Nurse P, Oliver K, Pearce J, Pelouchov J, Piccart M, Pinedo B, Spurrier-Bernard G, Sullivan R, Tabernero J, Van de Velde C, van Herk B, Vedsted P, Waldmann A, Weller D, Wilking N, Wilson R, Yared W, Zielinski C, Zur Hausen H, Le Chevalier T, Johnston P.
  ESMO OPEN 1, e000127-.
• Genetic validation of cell proliferation via Ras-independent activation of the Raf/Mek/Erk pathway.(2017)
  Lechuga CG, Simón-Carrasco L, Jacob HKC, Drosten M
  Methods Mol Biol 1487, 269-276.
• Lessons learnt from genetic studies in mice into Noonan syndrome.(2017)
  Schuhmacher AJ, Hernández-Porras I, García-Medina R, Guerra C
  Expert Review of Endocrinology and Metabolism 12, 367-378.
• Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma.(2016)
  Ambrogio C, Gómez-López G, Falcone M, Vidal A, Nadal E, Crosetto N, Blasco RB, Fernández-Marcos PJ, Sánchez-Céspedes M, Ren X, Wang Z, Ding K, Hidalgo M, Serrano M, Villanueva A, Santamaría D, Barbacid M
  Nat Med 22, 270-277.
• The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice.(2016)
  Martinelli P, Madriles F, Cañamero M, Pau EC, Pozo ND, Guerra C, Real FX.
  Gut 65, 476-486.
• K-Ras(V14I) -induced Noonan syndrome predisposes to tumour development in mice.(2016)
  Hernández-Porras I, Schuhmacher AJ, Garcia-Medina R, Jiménez B, Cañamero M, de Martino A, Guerra C
  J Pathol 239, 206-217.
• In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma.(2016)
  Ambrogio C, Barbacid M, Santamaría D
  Oncogene (in press).
• Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells.(2016)
  Augereau C, Collet L, Vargiu P, Guerra C, Ortega S, Lemaigre FP, Jacquemin P
  Hum Mol Genet 25, 5017-5026.
• Modeling K-Ras-driven lung adenocarcinoma in mice: preclinical validation of therapeutic targets.(2016)
  Drosten M, Barbacid M
  J Mol Med-Jmm 94, 121-135.
• An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia.(2016)
  Lopez S, Voisset E, Tisserand JC, Mosca C, Prebet T, Santamaria D, Dubreuil P, De Sepulveda P
  Oncotarget 7, 51163-51173.
• KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy.(2016)
  Ambrogio C, Nadal E, Villanueva A, Gómez-López G, Cash TP, Barbacid M, Santamaría D
  ESMO OPEN 1, e000076-.
• Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.(2015)
  García-Beccaria M, Martínez P, Méndez-Pertuz M, Martínez S, Blanco-Aparicio C, Cañamero M, Mulero F, Ambrogio C, Flores JM, Megias D, Barbacid M, Pastor J, Blasco MA
  EMBO Mol Med 7, 930-949.
• Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice.(2015)
  Lopez-Contreras AJ, Specks J, Barlow JH, Ambrogio C, Desler C, Vikingsson S, Rodrigo-Perez S, Green H, Rasmussen LJ, Murga M, Nussenzweig A, Fernandez-Capetillo O
  Genes Dev 29, 690-695.
• Functional reprogramming of polyploidization in megakaryocytes.(2015)
  Trakala M, Rodríguez-Acebes S, Maroto M, Symonds CE, Santamaría D, Ortega S, Barbacid M, Méndez J, Malumbres M.
  Dev Cell 32, 155-167.
• SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel Plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial.(2015)
  Hidalgo M, Plaza C, Musteanu M, Illei P, Brachmann CB, Heise C, Pierce DW, Lopez-Casas PP, Menendez C, Tabernero J, Romano A, Wei X, Lopez-Rios F, Von Hoff DD
  Clin Cancer Res 21, 4811-4818.
• Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency(2015)
  Ceccon M, Merlo ME, Mologni L, Poggio T, Varesio LM, Menotti M., Bombelli S, Rigolio R, Manazza AD, DiGiacomo F, Ambrogio C, Giudici G, Casati C, Mastini C, Compagno M, Turner SD, Gambacorti-Passerini C, Chiarle R, Voena C
  Oncogene (in press).
• Loss of p27Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.(2015)
  Jeannot P, Callot C, Romain Baer R, Duquesnes N, Guerra C, Guillermet-Guibert J, Bachs O, Besson A
  Oncotarget 6, 35880-35882.
• Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice.(2015)
  Pathria P, Gotthardt D, Prchal-Murphy M, Putz EM, Holcmann M, Schlederer M, Grabner B, Crncec I, Svinka J, Musteanu M, Hoffmann T, Filipits M, Berger W, Poli V, Kenner L, Bilban M, Casanova E, Müller M, Strobl B, Bayer E, Mohr T, Sexl V, Eferl R
  Oncoimmunology 4, e998529-.
• CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase.(2015)
  Viera A, Alsheimer M, Gómez R, Berenguer I, Ortega S, Symonds CE, Santamaría D, Benavente R, Suja JA
  J Cell Sci 128, 88-99.
• H-ras distribution and signaling in plasma membrane microdomains are regulated by acylation and deacylation events.(2015)
  Agudo-Ibáñez L, Herrero A, Barbacid M, Crespo P
  Mol Cell Biol 35, 1898-1914.
• Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors.(2015)
  Voena C, Menotti M, Mastini C, Di Giacomo F, Longo DL, Castella B, Merlo ME, Ambrogio C, Wang Q, Minero VG, Poggio T, Martinengo C, D'Amico L,Panizza E, Mologni L, Cavallo F, Altruda F, Butaney M,Capelletti M, Inghirami G, Jänne PA, Chiarle R
  Cancer Immunol Res 3, 1333-1343.
• Whole Exome Sequencing of Rapid Autopsy Tumors and Xenograft Models Reveals Possible Driver Mutations Underlying Tumor Progression.(2015)
  Xie T, Musteanu M, Lopez-Casas PP, Shields DJ, Olson P, Rejto PA, Hidalgo M
  PLoS ONE 10, e0142631-.
• Analysis of Murine Lung Tumors by Micro PET-CT Imaging.(2015)
  Ambrogio C, Cámara JA, Nieto P, Santamaría D, Mulero F
  Bioprotocol 5, E1692-.
• Ras and p53: an unsuspected liaison.(2015)
  Drosten M, Barbacid M
  Molecular Cellular Oncology (in press).
• The impact of the genetic background in the Noonan syndrome phenotype induced by K-Ras(V14I).(2015)
  Hernández-Porras I, Jiménez-Catalán B, Schuhmacher AJ, Guerra C
  RARE DISEASES 3, e1045169-.
• Nicotine Promotes Initiation and Progression of KRAS-Induced Pancreatic Cancer via Gata6-Dependent Dedifferentiation of Acinar Cells in Mice.(2014)
  Hermann PC, Sancho P, Cañamero M, Martinelli P, Madriles F, Michl P, Gress T, de Pascual R, Gandia L, Guerra C, Barbacid M, Wagner M, Vieira CR, Aicher A, Real FX, Sainz B Jr, Heeschen C
  Gastroenterology 147, 1119-1133.
• Concurrent deletion of cyclin E1 and cyclin-dependent kinase 2 in hepatocytes inhibits DNA replication and liver regeneration in mice.(2014)
  Hu W, Nevzorova YA, Haas U, Moro N, Sicinski P, Geng Y, Barbacid M, Trautwein C, Liedtke C
  Hepatology 59, 651-660.
• Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway.(2014)
  Drosten M, Sum EY, Lechuga CG, Simón-Carrasco L, Jacob HK, García-Medina R, Huang S, Beijersbergen RL, Bernards R, Barbacid M
  Proc Natl Acad Sci USA 111, 15155-15160.
• K-RasV14I recapitulates Noonan syndrome in mice.(2014)
  Hernández-Porras I, Fabbiano S, Schuhmacher AJ, Aicher A, Cañamero M, Cámara JA, Cussó L, Desco M, Heeschen C, Mulero F, Bustelo XR, Guerra C, Barbacid M
  Proc Natl Acad Sci USA 111, 16395-16400.
• Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma.(2014)
  Mainardi S, Mijimolle N, Francoz S, Vicente-Dueñas C, Sánchez-García I, Barbacid M
  Proc Natl Acad Sci USA 111, 255-260.
• Modeling Lung Cancer Evolution and Pre-Clinical Response By Orthotopic Mouse Allografts.(2014)
  Ambrogio C, Carmona FJ, Vidal A, Falcone M, Nieto P, Romero OA, Puertas S, Vizoso M, Nadal E, Poggio T, Sanchez-Cespedes M, Esteller M, Mulero F, Voena C, Chiarle R, Barbacid M, Santamaria D, Villanueva A
  Cancer Res 74, 5978-5988.
• Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation.(2014)
  Martínez-Bosch N, Fernández-Barrena MG, Moreno M, Ortiz-Zapater E, Munné-Collado J, Iglesias M, André S, Gabius HJ, Hwang RF, Poirier F, Navas C, Guerra C, Fernández-Zapico ME, Navarro P
  Cancer Res 74, 3512-3524.
• Ras signaling is essential for skin development.(2014)
  Drosten M, Lechuga CG, Barbacid M
  Oncogene 33, 2587-2865.
• Parp-1 genetic ablation in Ela-myc mice unveils novel roles for Parp-1 in pancreatic cancer.(2014)
  Martínez-Bosch N, Iglesias M, Munné-Collado J, Martínez-Cáceres C, Moreno M, Guerra C, Yélamos J, Navarro P
  J Pathol 234, 214-217.
• Ras in epidermal proliferation.(2014)
  Drosten M, Lechuga CG, Barbacid M
  Oncotarget 5, 5194-5195.
• A catalyst for change: the European cancer patient’s Bill of rights.(2014)
  Lawler M, Le Chevalier T, Murphy MJ Jr, Banks I, Conte P, De Lorenzo F, Meunier F, Pinedo HM, Selby P, Armand JP, Barbacid M, Barzach M, Bergh J, Bode G, Cameron DA, de Braud F, de Gramont A, Diehl V, Diler S, Erdem S, Fitzpatrick JM, Geissler J, Hollywood D, Højgaard L, Horgan D, Jassem J, Johnson PW, Kapitein P, Kelly J, Kloezen S, La Vecchia C, Löwenberg B, Oliver K, Sullivan R, Tabernero J, Van de Velde CJ, Wilking N, Wilson R, Zielinski C, Zur Hausen H, Johnston PG
  Oncologist 19, 217-224.
• Reply: ‘Comments on Stromal disrupting effects of nab-paclitaxel in pancreatic cancer’(2014)
  Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas PP, Megias D, Guerra C, Muñoz M, Quijano Y, Cubillo A, Rodriguez-Pascual J, Plaza C, de Vicente E, Prados S, Tabernero S, Barbacid M, Lopez-Rios F, Hidalgo M
  Br J Cancer 111, 1677-1678.
• Genetic characterization of the role of the Cip/Kip family of proteins as Cdk inhibitors and assembly factors.(2014)
  Cerqueira A, Martín A, Symonds CE, Odajima J, Dubus P, Barbacid M, Santamaría D
  Mol Cell Biol 34, 1452-1459.
• STAT3ß controls inflammatory responses and early tumor onset in skin and colon experimental cancer models.(2014)
  Marino F, Orecchia V, Regis G, Musteanu M, Tassone B, Jon C, Forni M, Calautti E, Chiarle R, Eferl R, Poli V
  Am J Cancer Res 4, 484-494.
• Lentiviral-based approach for the validation of cancer therapeutic targets in vivo.(2014)
  Ambrogio C, Stern P, Scuoppo C, Kranz H, Barbacid M, Santamaría D
  Biotechniques 57, 179-.
• Mouse models of cancer.(2013)
  Berns A, Barbacid M
  Mol Oncol 7, 232-247.
• Genetically engineered mouse models of pancreatic adenocarcinoma.(2013)
  Guerra C, Barbacid M
  Mol Oncol 7, 232-247.
• Stromal disrupting effects of nab-paclitaxel in pancreatic cancer.(2013)
  Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas PP, Megias D, Guerra C, Muñoz M, Quijano Y, Cubillo A, Rodriguez-Pascual J, Plaza C, de Vicente E, Prados S, Tabernero S, Barbacid M, Lopez-Rios F, Hidalgo M
  Br J Cancer 109, 926-933.
• Reversible, interrelated mRNA and miRNA expression patterns in the transcriptome of Rasless fibroblasts: functional and mechanistic implications.(2013)
  Azrak SS, Ginel-Picardo A, Drosten M, Barbacid M, Santos E
  Bmc Genomics 14, 731-.
• Lkb1 Loss Promotes Tumor Progression of BRAFV600E-Induced Lung Adenomas.(2013)
  González-Sánchez E, Martín-Caballero J, Flores JM, Hernández-Losa J; Ma Ángeles Montero, Cortés J, Mares R, Barbacid M, Recio JA
  PLoS ONE 8, e66933-.
• Genetic analysis of Ras genes in epidermal development and tumorigenesis.(2013)
  Drosten M, Lechuga CG, Barbacid M
  Small GTPases 4, 4-.