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

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. Acknowledgements: We thank Phil Mason for his help in correcting the English and Helena Pisonero (IDIVAL) for technical assistance in the lab. The research was supported by grants from the Instituto de Salud Carlos III, from the Ministerio de Economía, Industria y Competitividad [SAF2013-47416-R, CIBERONC-ISCIII, ISCIII-MINECO-AES-FEDER (Plan Estatal I + D + I 2013–2016)}. The AECC PROYE18054PIRI, CAM B2017/BMD-3778, PIC97/2017_FJD, PIE15/0081 and PIE16/01294; Asociación Española Contra el Cáncer (AECC), Comunidad Autónoma de Madrid and Instituto Formación e Investigación, Hospital Universitario Marqués de Valdecilla (IDIVAL): NVAL16/18. A E-C is funded by ISCIII /MINECO (PT17/0009/0019) and co-funded by FEDER.