Experimental Oncology Group

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

Staff Scientists

Matthias Drosten
Carmen Guerra

Post-Doctoral Fellows

Sara García
Federico Virga

Graduate Students

Gonzalo María Aizpurua
Oksana Brehey
Laura De la Puente
Sara Barrambana
Fernando Fernández
Ana María Fernández
Vasiliki Liaki
Lucía Morales
Marina Salmón
Pian Sun

Technicians

Ruth Álvarez
Mª Carmen González
Patricia Teresa Guerra
Silvia Jiménez
Alejandra López
Marta San Román
Raquel Villar

KRAS oncogenes have been identified in one-fifth of all human cancers. In 2020, selective inhibitors against one of the KRAS oncogenic isoforms, KRAS ^G12C, have been developed. Yet all the other isoforms remain undruggable. Moreover, selective inhibitors of KRAS signalling pathways have failed in the clinic due to unacceptable toxicities. Previous work in our laboratory, allowed us to identify RAF1 as the only effector within the MAPK pathway whose elimination induced significant tumour regressions without causing major toxicities. In 2020, we have identified CDK4 as a second potential therapeutic target. Combined RAF1 ablation and expression of a CDK4 kinase dead isoform completely prevented tumour progression of KRAS/TRP53 driven lung adenocarcinomas and led to complete regression of a quarter of these tumours without increasing overall toxicity. We trust that the identification of additional targets with potential therapeutic activity may eventually lead to the complete elimination of these aggressive tumours.

Publications

Paniagua G, Jacob HKC, Brehey O, García-Alonso S, Lechuga CG, Pons T, Musteanu M, Guerra C, Drosten M, Barbacid M. (2022). KSR induces RAS-independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors. Mol Oncol (in press). CNIO Publication.
Sanclemente M, Nieto P, Garcia-Alonso S, Fernández-García F, Esteban-Burgos L, Guerra C, Drosten M, Caleiras E, Martinez-Torrecuadrada J, Santamaría D, Musteanu M, Barbacid M (2021). RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression.. Cancer Cell 39, 294-296. CNIO Publication.
Assi M, Achouri Y, Loriot A, Dauguet N, Dahou H, Baldan J, Libert M, Fain JS, Guerra C, Bouwens L, Barbacid M, Lemaigre FP, Jacquemin P (2021). Dynamic Regulation of Expression of KRAS and Its Effectors Determines the Ability to Initiate Tumorigenesis in Pancreatic Acinar Cells. Cancer Res 81, 2679-2689. CNIO Publication.
Salmón M, Paniagua G, Lechuga CG, Fernández-García F, Zarzuela E, Álvarez-Díaz R, Musteanu M, Guerra C, Caleiras E, Muñoz J, Ortega S, Drosten M, Barbacid M (2021). KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform. Proc Natl Acad Sci USA 118, e2023112118. CNIO Publication.
Rosigkeit S, Kruchem M, Thies D, Kreft A, Eichler E, Boegel S, Jansky S, Siegl D, Kaps L, Pickert G, Haehnel P, Kindler T, Hartwig UF, Guerra C, Barbacid M, Schuppan D, Bockamp E. (2021). Definitive evidence for Club cells as progenitors for mutant Kras/Trp53-deficient lung cancer. Int J Cancer 149, 1670-1682. CNIO Publication.
Drosten M, Barbacid M (2021). Targeting KRAS mutant lung cancer: light at the end of the tunnel.. Mol Oncol (in press). CNIO Publication.
Köhler J, Zhao Y, Li J, Gokhale PC, Tiv HL, Knott AR, Wilkens MK, Soroko KM, Lin M, Ambrogio C, Musteanu M, Ogino A, Choi J, Bahcall M, Bertram AA, Chambers ES, Paweletz CP, Bhagwat SV, Manro JR, Tiu RV, Jänne PA (2021). ERK inhibitor LY3214996-based treatment strategies for RAS-driven lung cancer.. Mol Cancer Ther 20, 641-654. CNIO Publication.
Lechuga CG, Salmón M, Paniagua G, Guerra C, Barbacid M, Drosten M (2021). RASless MEFs as a Tool to Study RAS-Dependent and RAS-Independent Functions. Methods Mol Biol 2262, 335-346. CNIO Publication.
Drosten M, Barbacid M (2020). Targeting the MAPK Pathway in KRAS-Driven Tumors.. Cancer Cell 37, 543-550. CNIO Publication.
Esteban-Burgos L, Wang H, Nieto P, Zheng J, Blanco-Aparicio C, Varela C, Gómez-López G, Fernández-García F, Sanclemente M, Guerra C, Drosten M, Galán J, Caleiras E, Martínez-Torrecuadrada J, Fajas L, Peng SB, Santamaría D, Musteanu M, Barbacid M (2020). Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas. Proc Natl Acad Sci USA 117, 24415-24426. CNIO Publication.
Vitos-Faleato J, Real SM, Gutierrez-Prat N, Villanueva A, Llonch E, Drosten M, Barbacid M, Nebreda AR (2020). Requirement for epithelial p38? in KRAS-driven lung tumor progression.. Proc Natl Acad Sci USA 117, 2588-2596. CNIO Publication.
Nokin MJ, Darbo E, Travert C, Drogat B, Lacouture A, San José S, Cabrera N, Turcq B, Prouzet-Mauleon V, Falcone M, Villanueva A, Wang H, Herfs M, Mosteiro M, Jänne PA, Pujol JL, Maraver A, Barbacid M, Nadal E, Santamaría D, Ambrogio C (2020). Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma. JCI Insight 5, 137869. CNIO Publication.
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.
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.
Barbacid M (2019). On the right TRK: from oncogene discovery to cancer therapeutics. Ann Oncol 30, viii3-viii4. 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
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
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
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.