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Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia
Mitch Raponi1, Robert T Belly, Judith E Karp
1Veridex, LLC, Johnson and Johnson Company, San Diego, CA 9212, USA. mraponi1@vrxus.jnj.com
Background:
Farnesyl protein transferase inhibitors (FTIs) were originally developed to inhibit oncogenic ras, however it is now clear that there are several other potential targets for this drug class. The FTI tipifarnib (ZARNESTRA, R115777) has recently demonstrated clinical responses in adults with refractory and relapsed acute leukemias. This study was conducted to identify genetic markers and pathways that are regulated by tipifarnib in acute myeloid leukemia (AML).
Methods:
Tipifarnib-mediated gene expression changes in 3 AML cell lines and bone marrow samples from two patients with AML were analyzed on a cDNA microarray containing approximately 7000 human genes. Pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis tool.
Results:
The expression analysis identified a common set of genes that were regulated by tipifarnib in three leukemic cell lines and in leukemic blast cells isolated from two patients who had been treated with tipifarnib. Association of modulated genes with biological functional groups identified several pathways affected by tipifarnib including cell signaling, cytoskeletal organization, immunity, and apoptosis. Gene expression changes were verified in a subset of genes using real time RT-PCR. Additionally, regulation of apoptotic genes was found to correlate with increased Annexin V staining in the THP-1 cell line but not in the HL-60 cell line.
Conclusions:
The genetic networks derived from these studies illuminate some of the biological pathways affected by FTI treatment while providing a proof of principle for identifying candidate genes that might be used as surrogate biomarkers of drug activity.
Insights
Farnesyl protein transferase inhibitors (FTIs) like tipifarnib impact gene expression in acute myeloid leukemia (AML). This study identified key genetic pathways and potential biomarkers for FTI drug activity in AML.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Farnesyl protein transferase inhibitors (FTIs) were initially developed to target oncogenic ras.
- Emerging evidence suggests FTIs have broader therapeutic potential beyond ras inhibition.
- Tipifarnib, an FTI, has shown promise in clinical trials for refractory and relapsed acute leukemias.
Purpose of the Study:
- To identify genetic markers regulated by tipifarnib in acute myeloid leukemia (AML).
- To elucidate the biological pathways influenced by tipifarnib in AML.
Main Methods:
- Gene expression profiling using cDNA microarrays on AML cell lines and patient samples.
- Pathway analysis employing the Ingenuity Pathway Analysis tool.
- Validation of gene expression changes using real-time RT-PCR.
Main Results:
- Tipifarnib consistently modulated a common set of genes across AML cell lines and patient samples.
- Affected pathways include cell signaling, cytoskeletal organization, immunity, and apoptosis.
- Apoptotic gene regulation correlated with Annexin V staining in THP-1 cells, but not HL-60 cells.
Conclusions:
- Tipifarnib influences distinct genetic networks and biological pathways in AML.
- These findings provide a foundation for identifying surrogate biomarkers of FTI drug activity.
- Understanding these pathways enhances the potential of FTIs in leukemia treatment.
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