Farnesyl transferase inhibitor resistance probed by target mutagenesis.
Mutation in the target oncoprotein is a common mechanism of resistance to tyrosine kinase inhibitors, as exemplified by the many BCR/ABL mutations that thwart imatinib activity in patients with chronic myelogenous leukemia. It remains unclear whether normal cellular protein targets of chemotherapeutics will evolve drug resistance via mutation to a similar extent. We conducted an in vitro screen for resistance to lonafarnib, a farnesyl protein transferase inhibitor that blocks prenylation of a number of proteins important in cell proliferation, and identified 9 mutations clustering around the lonafarnib binding site. In patients treated with a combination of imatinib and lonafarnib, we identified farnesyl protein transferase mutations in residues identified in our screen. Substitutions at Y361 were found in patients prior to treatment initiation, suggesting that these mutants might confer a proliferative advantage to leukemia cells, which we were able to confirm in cell culture. In vitro mutagenesis of normal cellular enzymes can be exploited to identify mutations that confer chemotherapy resistance to novel agents.
Raz
Tal
T
Division of Hematology/Oncology, Children's Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Nardi
Valentina
V
Azam
Mohammad
M
Cortes
Jorge
J
Daley
George Q
GQ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D010865:Pilot Projects; D010879:Piperazines / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D011487:Protein Conformation; D017368:Protein Prenylation; D011725:Pyridines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D003986:Dibenzocycloheptenes
D001549:Benzamides; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D000068877:Imatinib Mesylate; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; C115354:lonafarnib; D003986:Dibenzocycloheptenes