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 panKRASG12X 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
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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
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 121, e2402913121. CNIO Publication.
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.
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.
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.
Open Access