Experimental Oncology Group

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

Staff Scientists

Matthias Drosten
Raquel García
Carmen Guerra
Monica Musteanu

Post-Doctoral Fellows

Sara García
Carolina Navas
Guillem Paniagua

Graduate Students

Laura De Esteban
Fernando Fernández
Jing Li
Vasiliki Liaki
Lucía Morales
Marina Salmón
Manuel Sanclemente

Technicians

Irene de Diego
Mª Carmen González
Patricia Teresa Guerra
Silvia Jiménez
Anna Köck
Marta San Román
Raquel Villar

KRAS oncogenes have been identified in at least one fifth of all human cancers. In spite of recent successes with checkpoint inhibitors, most KRAS mutant tumours, including lung adenocarcinomas, are still treated with cytotoxic compounds approved over 2 decades ago. Moreover, attempts to block KRAS oncogenic activity with selective inhibitors of the MEK kinase, a downstream effector, have turned out to be major failures. Two MEK inhibitors, Trametinib and Selumetinib, have failed to show significant anti-tumour activity in large phase III clinical trials due to unacceptable toxicities. In our laboratory, we have continued our quest to validate therapeutic targets using a new generation of genetically engineered mouse tumour models that allow us to evaluate their anti-tumour properties as well as their potential toxic effects in tumour- bearing mice. These studies have allowed the identification of c-RAF as a target capable of inducing significant tumour regressions in advanced KRAS/TRP53 mutant lung tumours without inducing major toxicities. These observations suggest that forthcoming c-RAF inhibitors may provide significant therapeutic benefits in the clinic.

Publications

Yao Z, Gao Y, Su W, Yaeger R, Tao J, Na N, Zhang Y, Zhang C, Rymar A, Tao A, Timaul NM, Mcgriskin R, Outmezguine NA, Zhao H, Chang Q, Qeriqi B, Barbacid M, de Stanchina E, Hyman DM, Bollag G, Rosen N (2019). RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med 25, 284-291. CNIO Publication.
Quilichini E, Fabre M, Dirami T, Stedman A, De Vas M, Ozguc O, Pasek RC, Cereghini S, Morillon L, Guerra C, Couvelard A, Gannon M, Haumaitre C (2019). Pancreatic ductal deletion of Hnf1b disrupts exocrine homeostasis, leads to pancreatitis and facilitates tumorigenesis.. Cell Mol Gastroenterol Hepatol 8, 487-511. CNIO Publication. Open Access
Barbacid M (2019). On the right TRK: from oncogene discovery to cancer therapeutics. Ann Oncol 30, viii3-viii4. CNIO Publication.
García-Gutiérrez L, Bretones G, Molina E, Arechaga I, Symonds C, Acosta JC, Blanco R, Fernández A, Alonso L, Sicinski P, Barbacid M, Santamaría D, León (2019). Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27. Sci Rep 9, 18693. CNIO Publication. Open Access
Blasco MT, Navas C, Martín-Serrano G, Graña-Castro O, Lechuga CG, Martín-Díaz L, Djurec M, Li Jing, Morales-Cacho L, Esteban-Burgos L, Perales-Patón J, Bousquet-Mur E, Castellano E, Jacob Harrys KC, Cabras L, Mustenau M, Drosten M, Ortega S, Mulero F, Sainz B, Dusetti N, Iovanna J, Sánchez-Bueno F, Hidalgo M, Khiabanian H, Hidalgo M, Rabadán R, Al-Shahrour F, Guerra C, Barbacid M (2019). Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF. Cancer Cell 35, 573-587. CNIO Publication.
Cussó L, Musteanu M, Mulero F, Barbacid M, Desco M (2019). Effects of a Ketogenic Diet on [18F]FDG-PET Imaging in a Mouse Model of Lung Cancer. Mol Imaging Biol 21, 279-285. CNIO Publication.
Moll HP, Mohrherr J, Blaas L, Musteanu M, Stiedl P, Grabner B, Zboray K, König M, Stoiber D, Rülicke T, Strehl S, Eferl R, Casanova E (2019). A Mouse Model to Assess STAT3 and STAT5A/B Combined Inhibition in Health and Disease Conditions. Cancers 11, E1226. CNIO Publication. Open Access
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 (2018). Allele-specific mechanisms of activation of MEK1 mutants determine their properties. Cancer Discovery 8, 648-651. CNIO Publication.
Moll HP, Pranz K, Musteanu M, Grabner B, Hruschka N, Mohrherr J, Aigner P, Stiedl P, Brcic L, Laszlo V, Schramek D, Moriggl R, Eferl R, Moldvay J, Dezso K, Lopez-Casas PP, Stoiber D, Hidalgo M, Penninger J, Sibilia M, Gyorffy B, Barbacid M, Dome B, Popper H, Casanova E (2018). Afatinib restrains K-RAS driven lung tumorigenesis. Sci Transl Med 10, 446. CNIO Publication.
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 (2018). Targeting galectin-1 inhibits pancreatic cancer progression by interrupting tumor-stroma cross-talk. Proc Natl Acad Sci USA 115, E3769-E3778. CNIO Publication.
Mayor-Ruiz C, Olbrich T, Drosten M, Lecona E, Vega-Sendino M, Ortega S, Dominguez O, Barbacid M, Ruiz S, Fernandez-Capetillo O (2018). ERF deletion rescues RAS deficiency in mouse embryonic stem cells. Genes Dev 32, 568-576. CNIO Publication. Open Access
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 (2018). c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling. Cancer Cell 33, 217-228. CNIO Publication.
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 (2018). Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc Natl Acad Sci USA 115, E1147-E1156. CNIO Publication.
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 (2018). Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma. Proc Natl Acad Sci USA 115, 9282-9287. CNIO Publication.
Drosten M, Guerra C, Barbacid M (2018). Genetically Engineered Mouse Models of K-Ras-Driven Lung and Pancreatic Tumors: Validation of Therapeutic Targets. Cold Spring Harb Perspect Med 8, a031542. CNIO Publication.
Cussó L, Musteanu M, Mulero F, Barbacid M, Desco M (2018). Effects of a Ketogenic Diet on [18F]FDG-PET Imaging in a Mouse Model of Lung Cancer. Mol Imaging Biol 21, 279-285. CNIO Publication.
Simón-Carrasco L, Jiménez G, Barbacid M, Drosten M (2018). The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer. Cell Cycle 17, 702-711. CNIO Publication.
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 (2017). A Braf kinase-inactive mutant induces lung adenocarcinoma.. Nature 548, 239-243. CNIO Publication.
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 (2017). Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.. Nature 548, 234-238. CNIO Publication.
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 (2017). Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.. Biol Psychiat 81, 179-192. CNIO Publication.
Simón-Carrasco L, Graña O, Salmón M, Jacob HKC, Gutierrez A, Jiménez G, Drosten M, Barbacid M (2017). Inactivation of Capicua in adult mice causes T cell lymphoblastic lymphoma. Genes Dev 31, 1456-1468. CNIO Publication.
Drosten M, Simón-Carrasco L, Hernández-Porras I, Lechuga CG, Blasco MT, Jacob HK, Fabbiano S, Potenza N, Bustelo XR, Guerra C, Barbacid M (2017). H-Ras and K-Ras oncoproteins induce different tumor spectra when driven by the same regulatory sequences.. Cancer Res 77, 707-718. CNIO Publication.
Forés M, Simón-Carrasco L, Ajuria L, Samper N, González-Crespo S, Drosten M, Barbacid M, Jiménez G (2017). A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer. PLoS Genet 13, e1006622. CNIO Publication.
Ambrogio C, Barbacid M, Santamaría D (2017). In vivo oncogenic conflicto triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma.. Oncogene 36, 2309-2318. CNIO Publication.
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 (2017). Cdk4 regulates adult neural stem cell proliferation and differentiation in response to insulin-IRS2 signals.. Stem Cells 35, 2403-2416. CNIO Publication.
Schreiber J, Grimbergen LA, Overwater I, Vaart TV, Stedehouder J, Schuhmacher AJ, Guerra C, Kushner SA, Jaarsma D, Elgersma Y (2017). Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models. Sci Rep 7, 1256. CNIO Publication.
Drosten M, Guerra C and Barbacid M (2017). 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).. Cold Spring Harbor Laboratory Press (in press). CNIO Publication.
Hernández-Porras I, Guerra C (2017). Modeling Rasopathies with genetically modified mouse models.. Methods Mol Biol 1487, 379-408. CNIO Publication.
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. (2017). The European Cancer Patient’s Bill of Rights, update and implementation 2016.. ESMO OPEN 1, e000127. CNIO Publication.
Lechuga CG, Simón-Carrasco L, Jacob HKC, Drosten M (2017). Genetic validation of cell proliferation via Ras-independent activation of the Raf/Mek/Erk pathway.. Methods Mol Biol 1487, 269-276. CNIO Publication.
Schuhmacher AJ, Hernández-Porras I, García-Medina R, Guerra C (2017). Lessons learnt from genetic studies in mice into Noonan syndrome.. Expert Review of Endocrinology and Metabolism 12, 367-378. CNIO Publication.
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 (2016). Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma.. Nat Med 22, 270-277. CNIO Publication.
Martinelli P, Madriles F, Cañamero M, Pau EC, Pozo ND, Guerra C, Real FX. (2016). The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice.. Gut 65, 476-486. CNIO Publication.
Hernández-Porras I, Schuhmacher AJ, Garcia-Medina R, Jiménez B, Cañamero M, de Martino A, Guerra C (2016). K-Ras(V14I) -induced Noonan syndrome predisposes to tumour development in mice.. J Pathol 239, 206-217. CNIO Publication.
Ambrogio C, Barbacid M, Santamaría D (2016). In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma.. Oncogene (in press). CNIO Publication.
Augereau C, Collet L, Vargiu P, Guerra C, Ortega S, Lemaigre FP, Jacquemin P (2016). Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells.. Hum Mol Genet 25, 5017-5026. CNIO Publication.
Drosten M, Barbacid M (2016). Modeling K-Ras-driven lung adenocarcinoma in mice: preclinical validation of therapeutic targets.. J Mol Med-Jmm 94, 121-135. CNIO Publication.
Lopez S, Voisset E, Tisserand JC, Mosca C, Prebet T, Santamaria D, Dubreuil P, De Sepulveda P (2016). An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia. Oncotarget 7, 51163-51173. CNIO Publication. Open Access
Ambrogio C, Nadal E, Villanueva A, Gómez-López G, Cash TP, Barbacid M, Santamaría D (2016). KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy.. ESMO OPEN 1, e000076. CNIO Publication.
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 (2015). Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.. EMBO Mol Med 7, 930-949. CNIO Publication.
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 (2015). Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice.. Genes Dev 29, 690-695. CNIO Publication.
Trakala M, Rodríguez-Acebes S, Maroto M, Symonds CE, Santamaría D, Ortega S, Barbacid M, Méndez J, Malumbres M. (2015). Functional reprogramming of polyploidization in megakaryocytes.. Dev Cell 32, 155-167. CNIO Publication.
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 (2015). 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.. Clin Cancer Res 21, 4811-4818. CNIO Publication.
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 (2015). Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency. Oncogene (in press). CNIO Publication.
Jeannot P, Callot C, Romain Baer R, Duquesnes N, Guerra C, Guillermet-Guibert J, Bachs O, Besson A (2015). Loss of p27Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression.. Oncotarget 6, 35880-35882. CNIO Publication.
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 (2015). Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice.. Oncoimmunology 4, e998529. CNIO Publication.
Viera A, Alsheimer M, Gómez R, Berenguer I, Ortega S, Symonds CE, Santamaría D, Benavente R, Suja JA (2015). CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase.. J Cell Sci 128, 88-99. CNIO Publication.
Agudo-Ibáñez L, Herrero A, Barbacid M, Crespo P (2015). H-ras distribution and signaling in plasma membrane microdomains are regulated by acylation and deacylation events.. Mol Cell Biol 35, 1898-1914. CNIO Publication.
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 (2015). Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors.. Cancer Immunol Res 3, 1333-1343. CNIO Publication.
Xie T, Musteanu M, Lopez-Casas PP, Shields DJ, Olson P, Rejto PA, Hidalgo M (2015). Whole Exome Sequencing of Rapid Autopsy Tumors and Xenograft Models Reveals Possible Driver Mutations Underlying Tumor Progression.. PLoS ONE 10, e0142631. CNIO Publication.
Ambrogio C, Cámara JA, Nieto P, Santamaría D, Mulero F (2015). Analysis of Murine Lung Tumors by Micro PET-CT Imaging.. Bioprotocol 5, E1692. CNIO Publication.
Drosten M, Barbacid M (2015). Ras and p53: an unsuspected liaison.. Molecular Cellular Oncology (in press). CNIO Publication.
Hernández-Porras I, Jiménez-Catalán B, Schuhmacher AJ, Guerra C (2015). The impact of the genetic background in the Noonan syndrome phenotype induced by K-Ras(V14I).. RARE DISEASES 3, e1045169. CNIO Publication.