Abstract
Dasatinib and nilotinib are active in imatinib-resistant chronic myelocytic leukemia (CML) and many patients undergo sequential treatment. We aimed at modeling sequential tyrosine kinase inhibitor (TKI) resistance in vitro to compare the sequences imatinib-nilotinib-dasatinib and imatinib-dasatinib-nilotinib. We designed an in vitro model for sequential TKI resistance in CML. Replicates of imatinib-resistant cell lines were treated with dasatinib or nilotinib. Second-line resistant replicates were exposed to third-line treatment. Growth of all replicates in all three lines of treatment was associated with T315I. However, T315I occurred with low abundance and did not increase during sequential treatment. Nilotinib second-line more often gave rise to sequential resistance compared with dasatinib due to pre-existing P-loop mutations, especially at suboptimal drug concentration. In contrast, mutations predisposing to dasatinib resistance such as F317C/V and V299L did not occur before dasatinib exposure. Nilotinib third-line did not overcome imatinib-dasatinib resistance due to pre-existing T315I or P-loop/V299L or P-loop/F317 exchanges. Dasatinib third-line suppressed imatinib-nilotinib-resistant replicates with residual sensitivity. Sequential acquisition of BCR-ABL drug resistance mutations in CML might be underestimated. Resistance to sequential TKI monotherapy in vitro more often was associated with stepwise acquisition of drug-specific compound mutations compared with T315I. Pre-existing mutations strongly limited the activity of both third-line treatments, and the activity of nilotinib second-line in vitro critically depended on drug concentration.
Highlights
A drawback of imatinib therapy in chronic myelocytic leukemia (CML) and Phþ acute lymphocytic leukemia (ALL) presented itself in emerging resistance toward imatinib, found to be caused by several molecular resistance mechanisms, in particular, by point mutations in the kinase domain of BCR-ABL [1]
Nilotinib secondline more often gave rise to sequential resistance compared with dasatinib due to pre-existing P-loop mutations, especially at suboptimal drug concentration
Mutations predisposing to dasatinib resistance such as F317C/V and V299L did not occur before dasatinib exposure
Summary
A drawback of imatinib therapy in chronic myelocytic leukemia (CML) and Phþ acute lymphocytic leukemia (ALL) presented itself in emerging resistance toward imatinib, found to be caused by several molecular resistance mechanisms, in particular, by point mutations in the kinase domain of BCR-ABL [1]. The second-generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib were shown to be active in imatinib-resistant disease including patients with BCR-ABL kinase mutations with. Given first-line in chronic phase CML, both compounds compare favorably to imatinib with respect to response rates and progression events [4, 5]. Clinical studies showed that these mutations identified in vitro (Q252H, E255K/V, V299L, F317L, and T315I for dasatinib; Y253H/F, E255K/V, F311I, T315I and F359C/V for nilotinib) were associated with less favorable response rates and emerged at the time of disease progression receiving second-line treatment [11,12,13]. Dasatinib or nilotinib are given as second- and third-line therapies in patients with CML with resistance or intolerance to imatinib. Our results reveal significant differences in response characteristics and evolution of individual mutations depending on the order and concentration of nilotinib and dasatinib, sequentially administered in identical replicates of imatinib-resistant cell lines
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
