Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia.
OBJECTIVE
Microarray technology was used to identify gene expression markers that predict response to the orally available farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in acute myelogenous leukemia (AML).


METHODS
Gene expression profiles from 58 bone marrow samples from a cohort of relapsed and refractory AML patients were analyzed on the Affymetrix U133A gene chip that contains approximately 22,000 genes.


RESULTS
Supervised statistical analysis identified eight gene expression markers that could predict patient response to tipifarnib. The most robust gene was the lymphoid blast crisis oncogene (AKAP13), which predicted response with an overall accuracy of 63%. This gene provided a negative predictive value of 93% and a positive predictive value of 31% (increased from 18%). AKAP13 was overexpressed in patients who were resistant to tipifarnib. When overexpressed in the HL60 and THP1 cell lines, AKAP13 increased the resistance to tipifarnib by approximately 5- to 7-fold.


CONCLUSIONS
Diagnostic gene expression signatures may be used to select a group of AML patients that might respond to tipifarnib.
Raponi
Mitch
M
Veridex, L.L.C. a Johnson & Johnson Company, San Diego, California 92121, USA. mraponi1@vrxus.jnj.com
Harousseau
Jean-Luc
JL
Lancet
Jeffrey E
JE
Löwenberg
Bob
B
Stone
Richard
R
Zhang
Yi
Y
Rackoff
Wayne
W
Wang
Yixin
Y
Atkins
David
D
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D015363:Quinolones / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015363:Quinolones; C402769:tipifarnib