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Identification of Tipifarnib Sensitivity Biomarkers in T-cell Acute Lymphoblastic Leukemia and T-cell Lymphoma

Abstract: Patients 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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Sci Rep . 2020 Apr 21;10(1):6721

Editorial: Nature Publishing Group

 Año de publicación: 2020

Nº de páginas: 11

Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s41598-020-63434-5

ISSN: 2045-2322

Proyecto español: SAF2013-47416-R

Url de la publicación: https://doi.org/10.1038/s41598-020-63434-5

Autores/as

ALONSO-ALONSO, RUTH

MONDÉJAR, RUFINO

MARTÍNEZ, NEREA

GARCÍA-DIAZ, NURIA

PÉREZ, CRISTINA

MERINO, DAVID

RODRÍGUEZ, MARTA

ESTEVE-CODINA, ANNA

FUSTE, BERTA

GUT, MARTA

BURROWS, FRANCIS

SCHOLZ, CATHERINE

GUALBERTO, ANTONIO

PIRIS, MIGUEL ÁNGEL