Ferrer, I. (Irene)
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- FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their coexpression may predict FGFR-targeted therapy efficacy(2020) Ojeda, L. (Laura); García, S. (Santiago); Vicent, S. (Silvestre); Zugazagoitia, J. (Jon); Quintanal-Villalonga, Á. (Álvaro); Carnero, A. (Amancio); Montuenga-Badia, L.M. (Luis M.); Molina-Pinelo, S. (Sonia); Guruceaga, E. (Elizabeth); Paz-Ares, L. (Luis); Ferrer, I. (Irene); López-Ríos, F. (Fernando); Muñoz-Galván, S. (Sandra); Marrugal, Á. (Ángela); Cirauqui, C. (Cristina)Background: Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success. Methods: In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study. Findings: We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression. Interpretation: Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy.
- YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib(American Thoracic Society, 2019) Behrens, C. (C.); Pajares, M.J. (María José); Gil-Bazo, I. (Ignacio); Pio, R. (Rubén); Garmendia, I. (Irati); Remirez, A. (Ana); Hermida-Prado, F. (Francisco); Agorreta, J. (Jackeline); Felip, E. (Enriqueta); Lavín, A. (Amaya); García-Pedrero, J.M. (Juana M.); Granda-Díaz, R. (Rocío); Bustelo, X.R. (Xose R.); Montuenga-Badia, L.M. (Luis M.); Bertolo, C. (Cristina); Moreno, H. (Haritz); Valencia, K. (Karmele); Paz-Ares, L. (Luis); Sanchez-Cespedes, M. (Montserrat); Alameda, D. (Daniel); Ferrer, I. (Irene); Wistuba, I.I. (Ignacio I.); Lecanda, F. (Fernando); Cuadrado, M. (Myriam); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Rodrigo, J.P. (Juan P.)Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non–small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.
- 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.
- YES1 is a druggable oncogenic target in SCLC(Elsevier, 2022) Redín, E. (Esther); Garrido-Martín, E. (Eva); Valencia, K. (Karmele); Redrado, M. (Miriam); Solórzano-Rendón, J.L. (José Luis); Carias, R. (Rafael); Echepare, M. (Mirari); Expósito, F. (Francisco); Serrano-Tejero, D. (Diego); Ferrer, I. (Irene); Nunez-Buiza, A. (Angel); Garmendia, I. (Irati); García-Pedrero, J.M. (Juana M.); Gurpide, A. (Alfonso); Paz-Ares, L. (Luis); Politi, K. (Katerina); Montuenga-Badia, L.M. (Luis M.); Calvo-González, A. (Alfonso)Introduction: SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis. Methods: Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patientderived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes. Results: Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/ monitoring. Conclusions: Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.
- Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism(Nature Research, 2022) Cintado, E. (Elisa); Retana, D. (Diana); Troulé, K. (Kevin); Fustero-Torre, C. (Coral); Miarka, L. (Lauritz); Monteiro, C. (Cátia); Mazarico-Gallego, J. (José); Aristu-Mendioroz, J.J. (José Javier); Jiménez-Roldán, L. (Luis); Sepúlveda, J.M. (Juan Manuel); Trejo, J.L. (José Luis); Pérez-Núñez, A. (Ángel); Hegarty, A. (Aisling); Perea-García, M. (María); Tezanos, P. (Patricia); Siegfried, A. (Aurore); Muela, P. (Pablo); Priego, N. (Neibla); de Pablos-Aragoneses, A. (Ana); Caleiras, E. (Eduardo); Graña-Castro, O. (Osvaldo); Paz-Ares, L. (Luis); Moreno, L.M. (Luis Miguel); Ferrer, I. (Irene); González-León, P. (Pedro); García-Gómez, P. (Pedro); Suárez, R. (Rocío); Baena, P. (Patricia); Álvaro-Espinosa, L. (Laura); Esteban, O. (Olga)Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understand- ing of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary mela- noma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.