Browsing by Author "Esteban-Burgos, Laura"
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Publication c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling(Cell Press, 2018-05-01) Sanclemente, Manuel; Francoz, Sarah; Esteban-Burgos, Laura; Bousquet-Mur, Emilie; Djurec, Magdolna; Lopez-Casas, Pedro P; Hidalgo, Manuel; Guerra, Carmen; Drosten, Matthias; Musteanu, Mónica; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía e Innovación (España); Comunidad de Madrid (España); Fundación AXAA quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.Publication c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling.(Cell Press, 2018-02-12) Sanclemente, Manuel; Francoz, Sarah; Esteban-Burgos, Laura; Bousquet-Mur, Emilie; Djurec, Magdolna; Lopez-Casas, Pedro P; Hidalgo, Manuel; Guerra, Carmen; Barbacid, Mariano; Musteanu, Mónica; Drosten, Matthias; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Comunidad de Madrid (España); Fundación AXA; Instituto de Salud Carlos IIIA quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.Publication Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF(Cell Press, 2019-04-15) Blasco, María Teresa; Navas, Carolina; Martín-Serrano, Guillermo; Graña Castro, Osvaldo; Lechuga, Carmen G; Martín-Díaz, Laura; Djurec, Magdolna; Li, Jing; Morales-Cacho, Lucia; Esteban-Burgos, Laura; Perales-Patón, Javier; Bousquet-Mur, Emilie; Castellano, Eva; Jacob, Harrys K C; Cabras, Lavinia; Musteanu, Mónica; Drosten, Matthias; Ortega, Sagrario; Mulero, Francisca; Sainz, Bruno; Dusetti, Nelson; Iovanna, Juan; Sanchez-Bueno, Francisco; Hidalgo, Manuel; Khiabanian, Hossein; Rabadan, Raul; Al-Shahrour, Fatima; Guerra, Carmen; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Ligue Nationale Contre le Cancer (Francia); NIH - National Cancer Institute (NCI) (Estados Unidos); Fundación La Caixa; Fundación AXAFive-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.Publication Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.(Cell Press, 2019-04-15) Blasco, María Teresa; Navas, Carolina; Martín-Serrano, Guillermo; Martín-Díaz, Laura; Li, Jing; Morales-Cacho, Lucia; Esteban-Burgos, Laura; Perales-Patón, Javier; Bousquet-Mur, Emilie; Castellano, Eva; Jacob, Harrys K C; Cabras, Lavinia; Sainz, Bruno; Dusetti, Nelson; Iovanna, Juan; Sánchez-Bueno, Francisco; Hidalgo, Manuel; Khiabanian, Hossein; Rabadán, Raul; Graña Castro, Osvaldo; Lechuga C, Lechuga CG; Djurec M, Djurec M; Musteanu, Mónica; Drosten, Matthias; Ortega Jimenez, Sagrario; Mulero, Francisca; Guerra, Carmen; Barbacid, Mariano; Al-Shahrour, Fatima; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Asociación Española Contra el Cáncer; Ligue Nationale Contre le Cancer (Francia); United States Department of Health and Human Services; Deutsche Forschungsgemeinschaft (Alemania); Ministerio de Ciencia e Innovación (España); Fundación La Caixa; Ministerio de Economía, Industria y Competitividad (España); Fundación AXAFive-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.Publication RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression.(Cell Press, 2021-01-28) Sanclemente, Manuel; Nieto, Patricia; Garcia-Alonso, Sara; Fernández-García, Fernando; Drosten, Matthias; Santamaria, David; Musteanu, Mónica; Guerra, Carmen; Esteban-Burgos, Laura; Caleiras, E; Martinez Torrecuadrada, Jorge Luis; Barbacid, Mariano; Caleiras, Eduardo; Martinez-Torrecuadrada, Jorge; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Government of Spain; Comunidad de Madrid (España); Fundación AXA; Asociación Española Contra el CáncerPublication Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.(National Academy of Sciences, 2020-09-29) Wang, Haiyun; Nieto, Patricia; Zheng, Jie; Gómez-López, Gonzalo; Fernández-García, Fernando; Sanclemente, Manuel; Drosten, Matthias; Galán, Javier; Fajas, Lluis; Peng, Sheng-Bin; Santamaria, David; Musteanu, Mónica; Esteban-Burgos, Laura; Blanco-Aparicio, Carmen; Varela, Carmen; Guerra, Carmen; Caleiras, E; Martinez Torrecuadrada, Jorge Luis; Barbacid, Mariano; Caleiras, Eduardo; Martínez-Torrecuadrada, Jorge; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Ministerio de Economía, Industria y Competitividad (España); Comunidad de Madrid (España); National Natural Science Foundation of China; Fundación AXAKRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.