Experimental Oncology Group

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

Research Scientists

Sara García
Carmen Guerra

Graduate Students

Domingo Acosta
Gonzalo María Aizpurua
Oksana Brehey
Laura De la Puente
Sara Barrambana
Ana María Fernández
Ana Galván
Lucía Lomba
Blanca Rosas
Pian Sun
Elena Zamorano

Technicians

Rebeca Barrero
Mª Carmen González
Silvia Jiménez
Teresa Laguna Lobo
Vasiliki Liaki
Alejandra López
Marta San Román
Raquel Villar

Visiting Scientist

Mónica Andrea Musteanu
Carolina Villarroya

The main thrust of our laboratory is to identify therapeutic strategies against KRAS mutant lung and pancreatic tumours. In recent years, inhibitors against KRAS oncoproteins selective for some of their mutations such as G12C and G12D, as well as panKRAS^G12X inhibitors active against all mutations, have been either approved by the FDA (sotorasib and adagrasib) or are undergoing clinical trials. Yet, their clinical efficacy is far from what was expected. In lung cancer patients, sotorasib does not increase overall survival compared to standard chemotherapy regimens due to the rapid appearance of tumour resistance. We have used genetically engineered mouse models of lung and pancreatic tumours to compare the therapeutic efficacy of KRAS ablation with that of KRAS inhibition, and to interrogate the molecular mechanism responsible for tumour resistance. Whereas ablation of KRAS oncogenes eliminates both lung and pancreatic tumours completely with no signs of tumour resistance, KRAS inhibition results in the rapid appearance of resistance as previously observed in human tumours. We are currently exploring whether inhibiting KRAS signalling at independent nodes within its downstream or upstream signalling pathways, as well as in orthogonal pathways, will not only increase tumour responses but also prevent the appearance of tumour resistance.

Publications

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 (in press). CNIO Publication. Open Access
Sarno F, Tenorio J, Perea S, Medina L, Pazo-Cid R, Juez I, Rocío Garcia-Carbonero, Feliu J, Guillen-Ponce C, Lopez-Casas PP, Guerra C, Duran Y, López-Acosta JF, Alonso C, Esquivell E, Dopazo A, DiAkshinthala D, Muthuswamy S, Lapunzina P, Bockorny B, Hidalgo M (2024). A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial.. Clin Cancer Res (in press). CNIO Publication.
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 (in press). CNIO Publication.
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.
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. Publication in other institutions.
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.
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.
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. Open Access
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. Open Access
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.