Grupo de Oncología Experimental

Mariano Barbacid Jefe de Grupo
T +34 912246933 (Ext 4000)
mbarbacid@cnio.es

Investigadores Científicos

Sara García
Carmen Guerra

Becarios Post-doctorales

Carolina Villarroya

Becarios Pre-Doctorales

Gonzalo María Aizpurua
Oksana Brehey
Laura De la Puente
Sara Barrambana
Ana María Fernández
Ana Galván
Vasiliki Liaki
Lucía Lomba
Pian Sun
Elena Zamorano

Técnicos de Laboratorio

Rebeca Barrero
Mª Carmen González
Silvia Jiménez
Alejandra López
Marta San Román
Raquel Villar

The main area of interest of our Group is to identify therapeutic strategies against KRAS mutant lung and pancreatic tumours. For almost 4 decades, KRAS oncoproteins were thought to be undruggable targets. However, selective KRAS inhibitors, at least against one of the KRAS oncogenic isoforms, KRAS^G12C, have been recently approved by the FDA. Yet patients develop drug resistance rather quickly indicating that successful treatment of KRAS mutant tumours will require combination with inhibitors of KRAS signalling pathways, such as the MAP kinase and the PI3 kinase pathways. Unfortunately, all inhibitors tested thus far in the clinic have failed due to excessive toxicities. A potential exception is RAF1. Ablation of this kinase induced significant levels of tumour regression with limited toxicities in experimental models. Ironically, the tumour-inducing effect of RAF1 is not mediated by its kinase activity. Hence, pharmacological targeting of RAF1 will require the use of strategies capable of degrading the protein. To identify such compounds, we have determined the tertiary structure of the full RAF1 protein using Cryo-Electron Microscopy (Cryo-EM) technologies. These results have identified structural vulnerabilities that will make it possible to design selective RAF1 degraders.

Publicaciones

Macaya I, Roman M, Welch C, Entrialgo-Cadierno R, Salmon M, Santos A, Feliu I, Kovalski J, Lopez I, Rodriguez-Remirez M, Palomino-Echeverria S, Lonfgren SM, Ferrero M, Calabuig S, Ludwig IA, Lara-Astiaso D, Jantus-Lewintre E, Guruceaga E, Narayanan S, Ponz-Sarvise M, Pineda-Lucena A, Lecanda F, Ruggero D, Khatri P, Santamaria E, Fernandez-Irigoyen J, Ferrer I, Paz-Ares L, Drosten M, Barbacid M, Gil-Bazo I, Vicent S. (2023). Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer. Nat Commun 14, 6332. Publicación CNIO.
Salmón M, Álvarez-Díaz R, Fustero-Torre C, Brehey O, Lechuga CG, Sanclemente M, Fernández-García F, López-García A, Martín-Guijarro MC, Rodríguez-Perales S, Bousquet-Mur E, Morales-Cacho L, Mulero F, Al-Shahrour F, Martínez L, Domínguez O, Caleiras E, Ortega S, Guerra C, Musteanu M, Drosten M, Barbacid M. (2023). Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.. J Clin Invest 133, e164413. Publicación CNIO.
Díaz-Alejo JF, April-Monn S, Cihova M, Buocikova V, Villalón López J, Urbanova M, Lechuga CG, Tomas M, Dubovan P, Sánchez BL, Páez SC, Sanjuanbenito A, Lobo E, Romio de la Heras E, Guerra C, de la Pinta C, Barreto Melian E, Rodríguez Garrote M, Carrato A, Ruiz-Cañas L, Sainz B Jr, Torres A, Smolkova B, Earl J. (2023). Establishment of Pancreatic Cancer-Derived Tumor Organoids and Fibroblasts From Fresh Tissue. J Vis Exp (in press). Publicación CNIO.
García-Alonso S, Mesa P, Ovejero LP, Aizpurua G, Lechuga CG, Zarzuela E, Santiveri CM, Sanclemente M, Muñoz J, Musteanu M, Campos-Olivas R, Martínez-Torrecuadrada J, Barbacid M, Montoya G. (2022). Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Mol Cell 82, 3438-3452. Publicación CNIO.
Diego-González L, Fernández-Carrera A, Igea A, Martínez-Pérez A, Real Oliveira MECD, Gomes AC, Guerra C, Barbacid M, González-Fernández Á, Simón-Vázquez R (2022). Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor. Cancers 14, 3102. Publicación CNIO.
Drosten M, Barbacid M. (2022). KRAS inhibitors: Going non-covalent.. Mol Oncol 16, 3911-3915. Publicación CNIO.
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 16, 3066-3081. Publicación CNIO. Open Access
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO. Open Access
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. Publicación CNIO.
Drosten M, Barbacid M (2021). Targeting KRAS mutant lung cancer: light at the end of the tunnel.. Mol Oncol (in press). Publicación CNIO. Open Access
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. Publicación CNIO.
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. Publicación CNIO.
Drosten M, Barbacid M (2020). Targeting the MAPK Pathway in KRAS-Driven Tumors.. Cancer Cell 37, 543-550. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
Barbacid M (2019). On the right TRK: from oncogene discovery to cancer therapeutics. Ann Oncol 30, viii3-viii4. Publicación CNIO.
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. Publicación CNIO. 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. Publicación CNIO. 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. Publicación CNIO. 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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO. 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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO.