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Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma
Ruth Alonso-Alonso1,2,3, Rufino Mondéjar1,2,4, Nerea Martínez1,2
1Departamento Hematopatología Translacional, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
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.
Insights
The farnesyltransferase inhibitor tipifarnib shows promise for treating T-cell leukemias and lymphomas (TCLs). Genetic mutations and protein markers like NOTCH1, p-ERK, and RelB may predict patient response to this targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- T-cell leukemias and lymphomas (TCLs) have poor prognoses and limited treatment options.
- Targeted therapies are needed to improve outcomes for TCL patients.
Purpose of the Study:
- To evaluate the therapeutic potential of the farnesyltransferase inhibitor tipifarnib in TCL.
- To identify genomic and immunohistochemical markers of tipifarnib sensitivity and resistance.
Main Methods:
- Screened 25 TCL cell lines for tipifarnib sensitivity.
- Conducted mutational analysis of TP53, NOTCH1, and DNMT3.
- Performed immunohistochemistry for p-ERK and RelB.
- Utilized RNA-sequencing to analyze pathway alterations.
Main Results:
- 60% of TCL cell lines were sensitive to tipifarnib, showing reduced viability, induced apoptosis, and cell cycle modification.
- NOTCH1 mutations were more frequent in sensitive cell lines (69.2%) compared to resistant ones (0%).
- p-ERK and RelB were identified as potential biomarkers for tipifarnib sensitivity and resistance, respectively.
Conclusions:
- Tipifarnib is a potential therapeutic option for T-cell leukemia and TCL.
- NOTCH1 mutations, p-ERK, and RelB expression levels can serve as predictive biomarkers for tipifarnib treatment efficacy.
