Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia.
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.
Raponi
Mitch
M
Veridex, LLC, Johnson and Johnson Company, San Diego, CA 9212, USA. mraponi1@vrxus.jnj.com
Belly
Robert T
RT
Karp
Judith E
JE
Lancet
Jeffrey E
JE
Atkins
David
D
Wang
Yixin
Y
D000208:Acute Disease; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects; D051231:Farnesyltranstransferase; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015363:Quinolones / Q000494:pharmacology*
D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib