Potent Transient Inhibition of BCR-ABL by Dasatinib Leads to Complete Cytogenetic Remissions in Patients with Chronic Myeloid Leukemia: Implications for Patient Management and Drug Development. (2006)

Abstract Dasatinib (Sprycel; formerly BMS-354825) is an oral multi-targeted SRC/ABL tyrosine kinase inhibitor that is approximately 325-fold more potent than imatinib, and has been recently approved by the US FDA for the treatment of imatinib-resistant and -intolerant Philadelphia chromosome-associated leukemias. In contrast to other tyrosine kinase inhibitors, pharmacokinetic analyses reveal that dasatinib has a short half-life (5–6 hours), with near-complete loss of BCR-ABL kinase activity inhibition eight hours after drug administration in patients with CML. Remarkably, patients treated with dasatinib as infrequently as once daily, five days per week, have achieved complete cytogenetic remission (CCyR). We tested transient BCR-ABL inhibition in vitro by assessing the sensitivity of the CML cell line K562 to short-term exposure of dasatinib. After as short as a 20-minute exposure to a clinically-relevant dasatinib concentration (100 nM), the majority of cells undergo apoptosis when analyzed after 48 hours, whereas a clinically-relevant concentration of imatinib (5 uM) failed to result in substantial cytotoxicity under these conditions. When higher concentrations (&gt;=12.5 uM) of imatinib were used that correct for differences in potency between imatinib and dasatinib, cytotoxicity at 48 hours after a 20-minute exposure was similar to that observed with dasatinib. These results exclude SRC family inhibition as a potential mediator of this effect, and were reproducible in a second CML cell line, KU-812. Importantly, cytotoxicity was not observed in BCR-ABL-negative leukemia cell lines under these conditions. Signiificantly, similar phenomenon was observed when an erlotinib-sensitive non-small cell lung cancer was exposed to high concentrations of erlotinib for 20 minutes. We assessed the degree of BCR-ABL kinase inhibition achieved in 20 patients with chronic phase CML who were treated with dasatinib once daily as part of a phase I clinical trial by quantifying the ratio of phospho-CRKL to CRKL (a BCR-ABL substrate) achieved in PBMCs harvested four hours after the first dose of dasatinib. We found a strong correlation between the magnitude of BCR-ABL kinase inhibition and the depth of response achieved. Notably, CCyR was achieved exclusively in four patients who experienced the deepest inhibition of BCR-ABL kinase activity activity. The current medical management of CML involves assessing the degree of cytogenetic response after 6–12 months of imatinib therapy before considering dose modifications of imatinib. While our findings will need to be validated prospectively in larger cohorts of patients, they suggest that it may be feasible to make early dose modifications based upon the degree of target inhibition following the initial dose of dasatinib, and thus maximize the likelihood of clinical benefit. Together, these findings have potentially significant implications not only for the optimal clinical management of CML patients, but also for the rational development of small molecule inhibitors of other cancer-associated tyrosine kinases, as well as our global understanding of cancer cell biology.