Integrating in vitro sensitivity and dose-response slope is predictive of clinical response to ABL kinase inhibitors in chronic myeloid leukemia.
BCR-ABL mutations result in clinical resistance to ABL tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Although in vitro 50% inhibitory concentration (IC(50)) values for specific mutations have been suggested to guide TKI choice in the clinic, the quantitative relationship between IC(50) and clinical response has never been demonstrated. We used Hill's equation for in vitro response of Ba/F3 cells transduced with various BCR-ABL mutants to determine IC(50) and the slope of the dose-response curve. We found that slope variability between mutants tracked with in vitro TKI resistance, provides particular additional interpretive value in cases where in vitro IC(50) and clinical response are disparate. Moreover, unlike IC(50) alone, higher inhibitory potential at peak concentration (IPP), which integrates IC(50), slope, and peak concentration (Cmax), correlated with improved complete cytogenetic response (CCyR) rates in CML patients treated with dasatinib. Our findings suggest a metric integrating in vitro and clinical data may provide an improved tool for BCR-ABL mutation-guided TKI selection.
Division of Hematology, Hadassah Medical Center, Jerusalem, Israel;
Vladimir
V
Vainstein
Christopher A
CA
Eide
Thomas
T
O'Hare
Ofir
O
Shukron
Brian J
BJ
Druker
D001549:Benzamides / Q000494:pharmacology*; D054316:Biomarkers, Pharmacological / Q000032:analysis; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015233:Models, Statistical; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D001549:Benzamides; D054316:Biomarkers, Pharmacological; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib