In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets.
Although the prognosis of pediatric leukemias has improved considerably, many patients still have relapses. Tipifarnib, a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n = 25). AML samples were significantly more sensitive to tipifarnib compared to B-cell precursor ALL (BCP ALL) or N BM samples. Within AML, French-American-British (FAB) M5 samples were most sensitive to tipifarnib. T-cell ALL samples were significantly more sensitive than BCP ALL and N BM samples. In AML there was a marked correlation between tipifarnib resistance and daunorubicin or etoposide resistance, but not to cytarabine or 6-thioguanine. RAS mutations were present in 32% of AML and 18% of ALL samples, but there was no correlation between RAS mutational status and sensitivity to tipifarnib. Future studies are needed to identify biomarkers predictive of tipifarnib sensitivity. In addition, clinical studies, especially in T-cell ALL, seem warranted.
Goemans
Bianca F
BF
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands. bf.goemans@vumc.nl
Zwaan
Christian M
CM
Harlow
Amy
A
Loonen
Anne H
AH
Gibson
Brenda E S
BE
Hählen
Karel
K
Reinhardt
Dirk
D
Creutzig
Ursula
U
Heinrich
Michael C
MC
Kaspers
Gertjan J L
GJ
D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015363:Quinolones; D051231:Farnesyltranstransferase; D015689:Oncogene Protein p21(ras); C402769:tipifarnib