Alonso Alonso, RuthMondéjar, RufinoMartínez, NereaGarcía Diaz, NuriaPérez, CristinaMerino, DavidRodríguez, MartaEsteve-Codina, AnnaFusté, BertaGut, MartaBurrows, FrancisScholz, CatherineVaqué, José PedroGualberto, AntonioPiris, Miguel A.2020-05-142020-05-142020Alonso-Alonso R, Mondéjar R, Martínez N, García-Diaz N, Pérez C, Merino D, Rodríguez M, Esteve-Codina A, Fuste B, Gut M, Burrows F, Scholz C, Vaqué JP, Gualberto A, Piris MÁ. Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma. Sci Rep. 2020; 10(1):6721. DOI: 10.1038/s41598-020-63434-52045-2322http://hdl.handle.net/10230/44537Patients diagnosed with T-cell leukemias and T-cell lymphomas (TCLs) still have a poor prognosis and an inadequate response to current therapies, highlighting the need for targeted treatments. We have analyzed the potential therapeutic value of the farnesyltransferase inhibitor, tipifarnib, in 25 TCL cell lines through the identification of genomic and/or immunohistochemical markers of tipifarnib sensitivity. More than half of the cell lines (60%) were considered to be sensitive. Tipifarnib reduced cell viability in these T-cell leukemia and TCL cell lines, induced apoptosis and modified the cell cycle. A mutational study showed TP53, NOTCH1 and DNMT3 to be mutated in 84.6%, 69.2% and 30.0% of sensitive cell lines, and in 62.5%, 0% and 0% of resistant cell lines, respectively. An immunohistochemistry study showed that p-ERK and RelB were associated as potential biomarkers of tipifarnib sensitivity and resistance, respectively. Data from RNA-seq show that tipifarnib at IC50 after 72 h downregulated a great variety of pathways, including those controlling cell cycle, metabolism, and ribosomal and mitochondrial activity. This study establishes tipifarnib as a potential therapeutic option in T-cell leukemia and TCL. The mutational state of NOTCH1, p-ERK and RelB could serve as potential biomarkers of tipifarnib sensitivity and resistance.application/pdfeng© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-020-63434-5BiomarkersCancerCancer geneticsCancer genomicsGeneticsHaematological cancerMolecular biologyMolecular medicineOncologyinfo:eu-repo/semantics/openAccess