Entrialgo-Cadierno, R. (Rodrigo)
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- Correction: The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer(2023) Halberg, N. (Nils); Vicent, S. (Silvestre); Vallejo-Blanco, A. (Adrián); Cueto-Ureña, C. (Cristina); Entrialgo-Cadierno, R. (Rodrigo); Vera, L. (Laura); Ambrogio, C. (Chiara); Vietti-Michelina, S. (Sandra); Cortés-Dominguez, I. (Iván); Scaparone, P. (Pietro); Lara-Astiaso, D. (David); Erice, O. (Oihane); Macaya, I. (Irati); Darbo, E. (Elodie); Feliu, I. (Iker); Morales-Urteaga, X. (Xabier); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Goñi-Salaverri, A. (Ainhoa); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés)
- FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted(Elsevier, 2021) Banales, J.M. (Jesús M.); Arozarena, I. (Imanol); Vicent, S. (Silvestre); Vallejo-Blanco, A. (Adrián); Evert, M. (Matthias); Ruiz-Fernandez-de-Cordoba, B. (Borja); O’Dell, M. (Michael); Entrialgo-Cadierno, R. (Rodrigo); Avila, M.A. (Matías Antonio); Perugorria, M.J. (María J.); Ponz-Sarvise, M. (Mariano); Erice, O. (Oihane); Macaya, I. (Irati); Feliu, I. (Iker); Guruceaga, E. (Elizabeth); Olaizola, P. (Paula); Ortiz-Espinosa, S. (Sergio); Muggli, A. (Alexandra); Hezel, A.F. (Aram F.); Lecanda, F. (Fernando); García-Fernández-de-Barrena, M. (Maite); Calvisi, D.F. (Diego F.)Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
- The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas(American Society for Clinical Investigation, 2020) Lu, J. (Jun); Sun, T.Q. (Tian-Qiang); Román, M. (Marta); Miguéliz-Basterra, I. (Itziar); Vicent, S. (Silvestre); Entrialgo-Cadierno, R. (Rodrigo); Mazur, P.K. (Pawel K.); Hausmann, S. (Simone); Ponz-Sarvise, M. (Mariano); Erice, O. (Oihane); Chen, C.Z. (Chang-Zheng); Sweet-Cordero, E.A. (E. Alejandro); Flores, N.M. (Natasha M.); Tathireddy, A. (Anuradha); Sayles, L.C. (Leanne C.); Fragoso, R. (Rita); Guruceaga, E. (Elizabeth); Razquin, N. (Nerea); Valencia, K. (Karmele); Fortes, P. (Puri); Vallejo, A. (Adrian); Lecanda, F. (Fernando); Kostyrko, K. (Kaja); Lee, A.G. (Alex G.)Few therapies are currently available for patients with KRAS-driven cancers, highlighting the need to identify new molecular targets that modulate central downstream effector pathways. Here we found that the microRNA (miRNA) cluster including miR181ab1 is a key modulator of KRAS-driven oncogenesis. Ablation of Mir181ab1 in genetically engineered mouse models of Kras-driven lung and pancreatic cancer was deleterious to tumor initiation and progression. Expression of both resident miRNAs in the Mir181ab1 cluster, miR181a1 and miR181b1, was necessary to rescue the Mir181ab1-loss phenotype, underscoring their nonredundant role. In human cancer cells, depletion of miR181ab1 impaired proliferation and 3D growth, whereas overexpression provided a proliferative advantage. Lastly, we unveiled miR181ab1-regulated genes responsible for this phenotype. These studies identified what we believe to be a previously unknown role for miR181ab1 as a potential therapeutic target in 2 highly aggressive and difficult to treat KRAS-mutated cancers.
- The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer(2023) Halberg, N. (Nils); Vicent, S. (Silvestre); Vallejo-Blanco, A. (Adrián); Cueto-Ureña, C. (Cristina); Entrialgo-Cadierno, R. (Rodrigo); Vera, L. (Laura); Ambrogio, C. (Chiara); Vietti-Michelina, S. (Sandra); Cortés-Dominguez, I. (Iván); Scaparone, P. (Pietro); Lara-Astiaso, D. (David); Erice, O. (Oihane); Macaya, I. (Irati); Darbo, E. (Elodie); Feliu, I. (Iker); Morales-Urteaga, X. (Xabier); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Goñi-Salaverri, A. (Ainhoa); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés)BackgroundThe discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC.MethodsGenetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models.ResultsPITPNC1 was increased in human LUAD and PDAC, and associated with poor patients' survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC.ConclusionsOur data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments.
- Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer(2023) Gil-Bazo, I. (Ignacio); Drosten, M. (Mathias); Barbacid, M. (Mariano); Kovalski, J. (Joanna); Pineda-Lucena, A. (Antonio); Román, M. (Marta); Jantus-Lewintre, E. (Eloisa); Calabuig-Fariñas, S. (Silvia); Vicent, S. (Silvestre); Ludwig, I.A. (Iziar Amaia); Entrialgo-Cadierno, R. (Rodrigo); Palomino-Echeverría, S. (Sara); Salmon, M. (Marina); Fernandez-Irigoyen, J. (Joaquín); Ruggero, D. (Davide); Lara-Astiaso, D. (David); Santos, A. (Alba); Ponz-Sarvise, M. (Mariano); Macaya, I. (Irati); Feliu, I. (Iker); Rodríguez-Remírez, M. (M.); Guruceaga, E. (Elizabeth); Paz-Ares, L. (Luis); Ferrer, I. (Irene); Narayanan, S. (Shruthi); Ferrero, M. (Macarena); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés); Lonfgren, S.M. (Shane M.); Santamaria, E. (Enrique); Khatri, P. (Purvesh)Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
- Systematic analysis of the novel effectors PITPNC1 and HMGCS1 in mutant KRAS tumours(Universidad de Navarra, 2023-02-16) Entrialgo-Cadierno, R. (Rodrigo); Vicent, S. (Silvestre)The discovery of functionally relevant KRAS effectors in lung and PDAC may yield novel molecular targets or mechanisms amenable to inhibition strategies. Here, we studied the role of PITPNC1 and its controlled network in the development and progression of both mutant KRAS-driven cancers. Genetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was done. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D and in vivo models. PITPNC1 was increased in human LUAD and PDAC, and associated with poor patients survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. PITPNC1 controlled a transcriptional signature that highly overlapped with a KRAS-regulated one. Notably, PITPNC1 loss induced autophagy by decreasing MYC protein expression and preventing mTOR localization to lysosomes. A JAK2 inhibitor was predicted as putative PITPNC1 inhibitor and also induced autophagy and displayed antiproliferative effect. Furthermore, its combination with a KRASG12C inhibitor elicited a substantial antitumor effect in LUAD and PDAC. Our data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism that regulates the KRAS downstream targets MYC and mTOR, and controls a druggable transcriptional network for combinatorial treatments.
- LAMC2 regulates key transcriptional and targetable effectors to support pancreatic cancer growth(AACR - American Association of Cancer Research, 2023) Erice, O. (Oihane); Narayanan, S. (Shruthi); Feliu, I. (Iker); Entrialgo-Cadierno, R. (Rodrigo); Malinova, A. (Antonia); Vicentini, C. (Caterina); Guruceaga, E. (Elizabeth); Delfino, P. (Pietro); Trajkovic-Arsic, M. (Marija); Moreno, H. (Haritz); Valencia, K. (Karmele); Blanco, E. (Ester); Macaya, I. (Irati); Ohlund, D. (Daniel); Khatri, P. (Purvesh); Lecanda, F. (Fernando); Scarpa, A. (Aldo); Siveke, J. (Jens); Corbo, V. (Vincenzo); Ponz-Sarvise, M. (Mariano); Vicent, S. (Silve); Vicent, S. (Silvestre)The identification of pancreatic ductal adenocarcinoma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here, we investigated the cellular, functional, and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies.