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, KRASG12C, 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.
Publications
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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.
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.
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