Browsing by MeSH term "Proto-Oncogene Proteins c-raf"
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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 Coexpression of p-IGF-1R and MMP-7 Modulates Panitumumab and Cetuximab Efficacy in RAS Wild-Type Metastatic Colorectal Cancer Patients(Elsevier, 2018-07) Alonso, Vicente; Escudero, Pilar; Fernandez-Martos, Carlos; Salud, Antonia; Mendez, Miguel; Gallego, Javier; Rodriguez, Jose-R; Martin-Richard, Marta; Fernandez-Plana, Julen; Manzano, Hermini; Mendez, Jose-Carlos; Zanui, Monserrat; Falcó, Esther; Gil-Raga, Mireia; Rojo, Federico; Cuatrecasas, Miriam; Feliu, Jaime; Garcia-Albeniz, Xabier; Maurel, JoanINTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/ non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as N70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95% CI: 0.11-0.52; P =. 0004) and with shorter OS in POSIBA (adjusted HR: 1 .67; 95% CI: 0.96-2.90; P =. 07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP.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 Early differential responses elicited by BRAFV600E in adult mouse models.(Nature Publishing Group, 2022-02-10) Bosso, Giuseppe; Lanuza-Gracia, Pablo; Piñeiro-Hermida, Sergio; Yilmaz, Merve; Serrano, Rosa; Blasco, MA; Comunidad de Madrid (España); Agencia Estatal de Investigación (España); World Cancer Research Fund International; Unión Europea. Comisión Europea. European Research Council (ERC); Botín FoundationThe BRAF gene is frequently mutated in cancer. The most common genetic mutation is a single nucleotide transition which gives rise to a constitutively active BRAF kinase (BRAFV600E) which in turn sustains continuous cell proliferation. The study of BRAFV600E murine models has been mainly focused on the role of BRAFV600E in tumor development but little is known on the early molecular impact of BRAFV600E expression in vivo. Here, we study the immediate effects of acute ubiquitous BRAFV600E activation in vivo. We find that BRAFV600E elicits a rapid DNA damage response in the liver, spleen, lungs but not in thyroids. This DNA damage response does not occur at telomeres and is accompanied by activation of the senescence marker p21CIP1 only in lungs but not in liver or spleen. Moreover, in lungs, BRAFV600E provokes an acute inflammatory state with a tissue-specific recruitment of neutrophils in the alveolar parenchyma and macrophages in bronchi/bronchioles, as well as bronchial/bronchiolar epithelium transdifferentiation and development of adenomas. Furthermore, whereas in non-tumor alveolar type II (ATIIs) pneumocytes, acute BRAFV600E induction elicits rapid p53-independent p21CIP1 activation, adenoma ATIIs express p53 without resulting in p21CIP1 gene activation. Conversely, albeit in Club cells BRAFV600E-mediated proliferative cue is more exacerbated compared to that occurring in ATIIs, such oncogenic stimulus culminates with p21CIP1-mediated cell cycle arrest and apoptosis. Our findings indicate that acute BRAFV600E expression drives an immediate induction of DNA damage response in vivo. More importantly, it also results in rapid differential responses of cell cycle and senescence-associated proteins in lung epithelia, thus revealing the early molecular changes emerging in BRAFV600E-challenged cells during tumorigenesis in vivo.Publication Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival.(Wiley, 2010-03-17) Drosten, Matthias; Dhawahir, Alma; Sum, Eleanor Y M; Urosevic, Jelena; Lechuga, Carmen G; Esteban, Luis M; Castellano, Esther; Guerra, Carmen; Santos, Eugenio; Barbacid, Mariano; Ministerio de Ciencia e Innovación (España); Comunidad de Madrid (España); Junta de Castilla y León (España); Ernst Schering Foundation; German Research Foundation (DFG); National Health and Medical Research Council (Australia)We have used mouse embryonic fibroblasts (MEFs) devoid of Ras proteins to illustrate that they are essential for proliferation and migration, but not for survival, at least in these cells. These properties are unique to the Ras subfamily of proteins because ectopic expression of other Ras-like small GTPases, even when constitutively active, could not compensate for the absence of Ras proteins. Only constitutive activation of components of the Raf/Mek/Erk pathway was sufficient to sustain normal proliferation and migration of MEFs devoid of Ras proteins. Activation of the phosphatidylinositol 3-kinase (PI3K)/PTEN/Akt and Ral guanine exchange factor (RalGEF)/Ral pathways, either alone or in combination, failed to induce proliferation or migration of Rasless cells, although they cooperated with Raf/Mek/Erk signalling to reproduce the full response mediated by Ras signalling. In contrast to current hypotheses, Ras signalling did not induce proliferation by inducing expression of D-type Cyclins. Rasless MEFs had normal levels of Cyclin D1/Cdk4 and Cyclin E/Cdk2. However, these complexes were inactive. Inactivation of the pocket proteins or knock down of pRb relieved MEFs from their dependence on Ras signalling to proliferate.Publication Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition.(2022-10-09) Guardamagna, Mora; Berciano-Guerrero, Miguel-Angel; Villaescusa-González, Beatriz; Perez-Ruiz, Elisabeth; Oliver, Javier; Lavado-Valenzuela, Rocío; Rueda-Dominguez, Antonio; Barragán, Isabel; Queipo-Ortuño, María IsabelGut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy-BRAF/MEK inhibitors-have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM's link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.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 SEOM clinical guideline for the management of cutaneous melanoma (2020).(2021-03-02) Majem, M; Manzano, J L; Marquez-Rodas, I; Mujika, K; Muñoz-Couselo, E; Pérez-Ruiz, E; de la Cruz-Merino, L; Espinosa, E; Gonzalez-Cao, M; Berrocal, AMelanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I-III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.Publication The P34G mutation reduces the transforming activity of K-Ras and N-Ras in NIH 3T3 cells but not of H-Ras(American Society for Biochemistry and Molecular Biology (ASBMB), 2004-08-06) Oliva-Martinez, Jose Luis; Zarich-Dimitrievich, Natasha; Martinez, Natalia; Jorge, Rocío; Castrillo, Antonio; Azañedo, Marta; Garcia-Vargas , Susana; Gutiérrez-Eisman, Silvia; Juarranz, Angeles; Boscá, Lisardo; Gutkind, J Silvio; Rojas-Cabañeros, Jose Maria; Instituto de Salud Carlos III; Ministerio de Ciencia y Tecnología (España)Ras proteins (H-, N-, and K-Ras) operate as molecular switches in signal transduction cascades controlling cell proliferation, differentiation, or apoptosis. The interaction of Ras with its effectors is mediated by the effector-binding loop, but different data about Ras location to plasma membrane subdomains and new roles for some docking/scaffold proteins point to signaling specificities of the different Ras proteins. To investigate the molecular mechanisms for these specificities, we compared an effector loop mutation (P34G) of three Ras isoforms (H-, N-, and K-Ras4B) for their biological and biochemical properties. Although this mutation diminished the capacity of Ras proteins to activate the Raf/ERK and the phosphatidylinositol 3-kinase/AKT pathways, the H-Ras V12G34 mutant retained the ability to cause morphological transformation of NIH 3T3 fibroblasts, whereas both the N-Ras V12G34 and the K-Ras4B V12G34 mutants were defective in this biological activity. On the other hand, although both the N-Ras V12G34 and the K-Ras4B V12G34 mutants failed to promote activation of the Ral-GDS/Ral A/PLD and the Ras/Rac pathways, the H-Ras V12G34 mutant retained the ability to activate these signaling pathways. Interestingly, the P34G mutation reduced specifically the N-Ras and K-Ras4B in vitro binding affinity to Ral-GDS, but not in the case of H-Ras. Thus, independently of Ras location to membrane subdomains, there are marked differences among Ras proteins in the sensitivity to an identical mutation (P34G) affecting the highly conserved effector-binding loop.Publication 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.Publication Validation of dynamic risk stratification and impact of BRAF in risk assessment of thyroid cancer, a nation-wide multicenter study(Frontiers Media, 2023-01) Pérez-Fernández, Laura; Sastre, Julia; Zafón, Carles; Oleaga, Amelia; Castelblanco, Esmeralda; Capel, Ismael; Galofré, Juan C; Guadalix-Iglesias, Sonsoles; De la Vieja, Antonio; Riesco-Eizaguirre, Garcilaso; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; Centro de Investigación Biomédica en Red - CIBERONC (Cáncer); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Introduction: The dynamic risk stratification (DRS) is a relatively new system in thyroid cancer that considers the response to primary treatment to improve the initial risk of recurrence. We wanted to validate DRS system in a nationwide multicenter study and explore if the incorporation of BRAFV600E into DRS helps to better categorize and predict outcomes. Materials and methods: Retrospective study of 685 patients from seven centers between 1991 and 2016, with a mean age of 48 years and a median follow-up time of 45 months (range 23-77). The overall BRAFV600E prevalence was 53.4%. We classified patients into four categories based on DRS ('excellent', 'indeterminate', 'biochemical incomplete', and 'structural incomplete' response). Cox regression was used to calculate adjusted hazard ratios (AHR) and proportions of variance explained (PVEs). Results: We found 21.6% recurrences and 2.3% cancer-related deaths. The proportion of patients that developed recurrence in excellent, indeterminate, biochemical incomplete and structural incomplete response to therapy was 1.8%, 54%, 91.7% and 96.2% respectively. Considering the outcome at the end of the follow up, patients showed no evidence of disease (NED) in 98.2, 52, 33.3 and 25.6% respectively. Patients in the structural incomplete category were the only who died (17.7%). Because they have similar outcomes in terms of NED and survival, we integrated the indeterminate and biochemical incomplete response into one unique category creating the 3-tiered DRS system. The PVEs of the AJCC/TNM staging, ATA risk classification, 4-tiered DRS, and 3-tiered DRS to predict recurrence at five years were 21%, 25%, 57% and 59% respectively. BRAFV600E was significantly associated with biochemical incomplete response (71.1 vs 28.9%) (HR 2.43; 95% CI, 1.21 to 5.23; p=0.016), but not with structural incomplete response or distant metastases. BRAF status slightly changes the AHR values of the DRS categories but is not useful for different risk grouping. Conclusions: This is the first multicenter study to validate the 4-tiered DRS system. Our results also show that the 3-tiered DRS system, by integrating indeterminate and biochemical incomplete response into one unique category, may simplify response to therapy keeping the system accurate. BRAF status does not provide any additional benefit to DRS.