Experimental Oncology Group

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

Research Scientists

Sara García
Carmen Guerra

Post-Doctoral Fellows

Juan Carlos López

Graduate Students

Domingo Acosta
Gonzalo María Aizpurua
Oksana Brehey
Ana María Fernández
Ana Galván
Lucía Lomba
Blanca Rosas
Andrés Simón
Pian Sun
Elena Zamorano

Technicians

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

Visiting Scientist

Matthias Drosten
Mónica Andrea Musteanu

For over three decades, KRAS proteins were thought to be undruggable. This concept came to an end when, in 2013, Shokat and co-workers identified a small groove in the KRAS^G12C oncoprotein, which allows the insertion of small inhibitory chemotypes. These results led to a frenetic race to develop a new generation of KRAS inhibitors. Unfortunately, these inhibitors have provided somewhat disappointing results in the clinic, primarily due to the rapid onset of tumour resistance. In our laboratory, we reasoned that the most efficacious way to overcome tumour resistance was to target KRAS signalling at independent nodes, thus thwarting the capacity of tumour cells to utilise alternative pathways that bypass the anti-tumoural effect of KRAS inhibitors. This strategy has proved to be correct. Indeed, we have recently demonstrated that the genetic ablation of three independent nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS signalling led to the complete and permanent regression of experimental pancreatic tumours. More importantly, we have successfully translated these results to a pharmacological scenario. We have reported that a combination of KRAS, EGFR and STAT3 inhibitors induced the complete and durable regression of experimental and patient-derived (PDX) pancreatic tumour models. These results should guide the development of new clinical trials to benefit pancreatic cancer patients.

Recent publications

Liaki V, Barrambana S, Kostopoulou M, Lechuga CG, Zamorano-Dominguez E, Acosta-Gallego D, Morales-Cacho L, Álvarez R, Sun P, Rosas-Perez B, Barrero R, Jiménez-Parrado S, López-García A, San Roman M, López-Gil JC, Drosten M, Sainz B Jr, Musteanu M, Caleiras E, Dusetti N, Poli V, Sánchez-Bueno F, Guerra C, Barbacid M. (2026). A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. Proc Natl Acad Sci USA 123, e2610708123. CNIO Publication.
Chen D, Lu S, Huang K, Pearson JD, Pacal M, Peidis P, McCurdy S, Yu T, Sangwan M, Nguyen A, Monnier PP, Schramek D, Zhu L, Santamaria D, Barbacid M, Akeno N, Wikenheiser-Brokamp KA, Bremner R. (2025). Cell cycle duration determines oncogenic transformation capacity. Nature 641, 1309-1318. CNIO Publication.
Barrambana S, Zamorano-Domínguez E, Liaki V, Guerra C. (2025). Navigating the complexities of pancreatic ductal adenocarcinoma: A review on therapeutic models and RAS inhibitors. Adv Drug Deliver Rev 224, 115652. CNIO Publication.
Sarno F, Tenorio J, Perea S, Medina L, Pazo-Cid R, Juez I, Garcia-Carbonero R, Feliu J, Guillen-Ponce C, Lopez-Casas PP, Guerra C, Duran Y, López-Acosta JF, Alonso C, Esquivel E, Dopazo A, Akshinthala D, Muthuswamy SK, Lapunzina P, Bockorny B, Hidalgo M. (2025). A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial.. Clin Cancer Res 31, 278-287. CNIO Publication.
Ballesteros-González I, Hernández-Navas I, Brehey O, Lechuga CG, Salmón M, Scotece M, Velasco-Vicente R, Flores-Gómez AA, Cebriá A, Simón-Carrasco L, Jiménez G, Musteanu M, Guerra C, Domínguez O, Caleiras E, Blanco-Aparicio C, Pons T, Ferrer I, Paz-Ares L, Torres-Ruiz R, Rodríguez-Perales S, Barbacid M, Drosten M. (2025). The repressor Capicua is a barrier to lung tumor development driven by Kras/Trp53 mutations. EMBO Mol Med 17, 3377-3406. CNIO Publication.
López-Merino E, Fernández-Rodrigo A, Jiang JG, Gutiérrez-Eisman S, Fernández de Sevilla D, Fernández-Medarde A, Santos E, Guerra C, Barbacid M, Esteban JA, Briz V. (2025). Different Ras isoforms regulate synaptic plasticity in opposite directions. EMBO J 44, 2103-2133. CNIO Publication.
Zamorano-Dominguez E, Morales-Cacho L, Barrero R, Jiménez-Parrado S, Dhawahir A, Hernández-Porras I, Simón-Carrasco L, Barrambana S, Sun P, Galván-Del-Rey A, Rosas-Perez B, Liaki V, Drosten M, Musteanu M, Virga F, Santos E, Mulero F, Caleiras E, Guerra C, Barbacid M. (2025). Systemic Kras ablation disrupts myeloid cell homeostasis in adult mice. Proc Natl Acad Sci USA 122, e2512404122. CNIO Publication.
Cirauqui C, Ojeda L, Otano I, Pazos I, Santos A, Garrido-Martín EM, Yagüe P, Ramos-Paradas J, Molina-Pinelo S, Roncador G, Solórzano JL, Muñoz MT, Cozar P, Plaza P, Suárez R, Jiménez M, Moreno R, Rosado A, Gámez P, García-Luján R, Zugazagoitia J, Sweet-Cordero EA, Barbacid M, Carnero A, Ferrer I, Paz-Ares L. (2025). Interleukin-11 promotes lung adenocarcinoma tumourigenesis and immune evasion. Clin Transl Med 15, e70374. CNIO Publication.
Fernández-Pisonero I, Lorenzo-Martín LF, Drosten M, Santos E, Barbacid M, Alarcón B, Bustelo XR. (2025). Active R-RAS2/TC21 prevents cell cycle arrest and morphological alterations in mouse embryonic fibroblasts lacking RAS proteins. Oncogene 44, 1905-1921. CNIO Publication. Open Access
Liaki V, Rosas-Perez B, Guerra C (2025). Unlocking the Genetic Secrets of Pancreatic Cancer: KRAS Allelic Imbalances in Tumor Evolution. Cancers 17, 1226. CNIO Publication.
Drosten M, Barbacid M. (2025). The rapidly growing landscape of RAS inhibitors: from selective allele blockade to broad inhibition strategies. Mol Oncol 19, 2991-2995. CNIO Publication.
Briones AC, Del Estal L, Villa-Gómez C, Bermejo V, Cervera I, Gutiérrez-Huerta P, Montes-Casado M, Ortega S, Barbacid M, Rojo JM, Portolés P. (2025). T Cell-Specific Inactivation of the PI3K p110α Catalytic Subunit: Effect in T Cell Differentiation and Antigen-Specific Responses. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 26, 595. CNIO Publication.
López-Gil JC, García-Silva S, Ruiz-Cañas L, Navarro D, Palencia-Campos A, Giráldez-Trujillo A, Earl J, Dorado J, Gómez-López G, Monfort-Vengut A, Alcalá S, Gaida MM, García-Mulero S, Cabezas-Sáinz P, Batres-Ramos S, Barreto E, Sánchez-Tomero P, Vallespinós M, Ambler L, Lin ML, Aicher A, García García de Paredes A, de la Pinta C, Sanjuanbenito A, Ruz-Caracuel I, Rodríguez-Garrote M, Guerra C, Carrato A, de Cárcer G, Sánchez L, Nombela-Arrieta C, Espinet E, Sanchez-Arevalo Lobo VJ, Heeschen C, Sainz B Jr. (2024). The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells. Gut 73, 1489-1508. CNIO Publication. Open Access
Fernández-García F, Fernández-Rodríguez A, Fustero-Torre C, Piñeiro-Yáñez E, Wang H, Lechuga CG, Callejas S, Álvarez R, Lopez-García A, Esteban-Burgos L, Salmón M, San Román M, Guerra C, Ambrogio Ch, Drosten M, Santamaria D, Al-Shahrour F, Dopazo A, Barbacid M, Musteanu M (2024). Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors. Proc Natl Acad Sci USA 121, e2402913121. CNIO Publication. Open Access
Rodrigo-Faus M, Vincelle-Nieto A, Vidal N, Puente J, Saiz-Pardo M, Lopez-Garcia A, Mendiburu-Eliçabe M, Palao N, Baquero C, Linzoain-Agos P, Cuesta AM, Qu HQ, Hakonarson H, Musteanu M, Reyes-Palomares A, Porras A, Bragado P, Gutierrez-Uzquiza A. (2024). CRISPR/Cas9 screenings unearth protein arginine methyltransferase 7 as a novel essential gene in prostate cancer metastasis. Cancer Lett 588, 216776. CNIO Publication.
Verstraelen P, Van Remoortel S, De Loose N, Verboven R, Garcia-Diaz Barriga G, Christmann A, Gries M, Bessho S, Li J, Guerra C, Tükel Ç, Martinez SI, Schäfer KH, Timmermans JP, De Vos WH (2024). Serum Amyloid A3 Fuels a Feed-Forward Inflammatory Response to the Bacterial Amyloid Curli in the Enteric Nervous System. Cell Mol Gastroenterol Hepatol 18, 89-104. CNIO Publication. Open Access
Arora M, Moser J, Hoffman TE, Watts LP, Min M, Musteanu M, Rong Y, Ill CR, Nangia V, Schneider J, Sanclemente M, Lapek J, Nguyen L, Niessen S, Dann S, VanArsdale T, Barbacid M, Miller N, Spencer SL (2023). Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. Cell 186, 2623-2643. CNIO Publication. Open Access
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. CNIO Publication.
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. CNIO Publication. Open Access
Janssen K, Claes F, Van de Velde D, Wehbi VL, Houben B, Lampi Y, Nys M, Khodaparast L, Khodaparast L, Louros N, van der Kant R, Verniers J, Garcia T, Ramakers M, Konstantoulea K, Maragkou K, Duran-Romaña R, Musteanu M, Barbacid M, Scorneaux B, Beirnaert E, Schymkowitz J, Rousseau F (2023). Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein. Proc Natl Acad Sci USA 120, e2214921120. CNIO Publication. Open Access
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 195, e65229. CNIO Publication.
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. CNIO Publication. Open Access
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. CNIO Publication. Open Access
Drosten M, Barbacid M. (2022). KRAS inhibitors: Going non-covalent.. Mol Oncol 16, 3911-3915. CNIO Publication. Open Access
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. CNIO Publication. 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. CNIO Publication. Open Access
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. 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. CNIO Publication. Open Access
Drosten M, Barbacid M (2021). Targeting KRAS mutant lung cancer: light at the end of the tunnel.. Mol Oncol (in press). CNIO Publication. 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. 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.