Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance. Safe and effective treatment modalities targeting leukemic clones that escape TKI therapy could hence be game changers in the professional management of these patients. Here, we aimed to investigate the efficacy of a novel therapeutic oligonucleotide of unconventional design, called ASP210, to reduce BCR-ABL1 mRNA levels in TKI-resistant CML cells, with the assumption of inducing their apoptosis. Imatinib- and dasatinib-resistant sublines of BCR-ABL1-positive MOLM-7 and CML-T1 cells were established and exposed to 0.25 and 2.5 µM ASP210 for 10 days. RT-qPCR showed a remarkable reduction of the target mRNA level by >99% after a single application. Cell viability was monitored daily by trypan blue staining. In response to the lack of driver oncoprotein BCR-ABL1, TKI-resistant CML cells underwent apoptosis regardless of the presence of the clinically relevant T315I mutation by day 5 after redosing with ASP210. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. Furthermore, the spontaneous uptake and high intracellular concentrations of ASP210 suggest its potential to be effective at relatively low doses. The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.NEW & NOTEWORTHY Effective treatment modalities targeting leukemic clones that escape tyrosine kinase inhibitor (TKI) therapy could be game changers in the professional management of patients displaying primary resistance, intolerance, or acquired resistance to TKIs. Although delivering authentic innovations today is more complex than ever, we developed a highly potent and safe oligonucleotide-based modality against BCR-ABL1 mRNA named ASP210 that effectively induces cell death in BCR-ABL1-positive TKI-resistant cells while sparing BCR-ABL1-negative healthy cells.

• Keywords
• BCR-ABL1, chronic myelogenous leukemia, oligonucleotide therapeutics, resistance to therapy, tyrosine kinase inhibitors,
• MeSH
• Apoptosis * drug effects   MeSH
• Fusion Proteins, bcr-abl * genetics   antagonists & inhibitors   metabolism   MeSH
• Drug Resistance, Neoplasm * drug effects   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   genetics   pathology   MeSH
• Dasatinib pharmacology   MeSH
• Imatinib Mesylate * pharmacology   therapeutic use   MeSH
• Protein Kinase Inhibitors * pharmacology   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Oligonucleotides * pharmacology   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fusion Proteins, bcr-abl * MeSH
• BCR-ABL1 fusion protein, human MeSH Browser
• Dasatinib MeSH
• Imatinib Mesylate * MeSH
• Protein Kinase Inhibitors * MeSH
• RNA, Messenger MeSH
• Oligonucleotides * MeSH
• Antineoplastic Agents MeSH

Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.

• MeSH
• Cisplatin * pharmacology   MeSH
• Dasatinib * pharmacology   chemistry   chemical synthesis   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds pharmacology   chemistry   chemical synthesis   MeSH
• Prodrugs * pharmacology   chemistry   chemical synthesis   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Drug Screening Assays, Antitumor MeSH
• Drug Synergism * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cisplatin * MeSH
• Dasatinib * MeSH
• Organoplatinum Compounds MeSH
• Prodrugs * MeSH
• Antineoplastic Agents * MeSH

Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.

• MeSH
• Administration, Oral MeSH
• Biological Availability MeSH
• Dasatinib MeSH
• Cross-Over Studies MeSH
• Humans MeSH
• Omeprazole * pharmacokinetics   MeSH
• Area Under Curve MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dasatinib MeSH
• Omeprazole * MeSH

The TcK2 protein kinase of Trypanosoma cruzi, the causative agent of Chagas disease, is structurally similar to the human kinase PERK, which phosphorylates the initiation factor eIF2α and, in turn, inhibits translation initiation. We have previously shown that absence of TcK2 kinase impairs parasite proliferation within mammalian cells, positioning it as a potential target for treatment of Chagas disease. To better understand its role in the parasite, here we initially confirmed the importance of TcK2 in parasite proliferation by generating CRISPR/Cas9 TcK2-null cells, albeit they more efficiently differentiate into infective forms. Proteomics indicates that the TcK2 knockout of proliferative forms expresses proteins including trans-sialidases, normally restricted to infective and nonproliferative trypomastigotes explaining decreased proliferation and better differentiation. TcK2 knockout cells lost phosphorylation of eukaryotic initiation factor 3 and cyclic AMP responsive-like element, recognized to promote growth, likely explaining both decreased proliferation and augmented differentiation. To identify specific inhibitors, a library of 379 kinase inhibitors was screened by differential scanning fluorimetry using a recombinant TcK2 encompassing the kinase domain and selected molecules were tested for kinase inhibition. Only Dasatinib and PF-477736, inhibitors of Src/Abl and ChK1 kinases, showed inhibitory activity with IC50 of 0.2 ± 0.02 mM and 0.8 ± 0.1, respectively. In infected cells Dasatinib inhibited growth of parental amastigotes (IC50 = 0.6 ± 0.2 mM) but not TcK2 of depleted parasites (IC50 > 34 mM) identifying Dasatinib as a potential lead for development of therapeutics for Chagas disease targeting TcK2.

• Keywords
• T.cruzi EIF2AK2, chagas disease, chemical inhibitor, eIF2α, invasion, protein kinase, proteome, recombinant protein,
• MeSH
• Chagas Disease * drug therapy   parasitology   MeSH
• Dasatinib MeSH
• eIF-2 Kinase genetics   metabolism   MeSH
• Humans MeSH
• Parasites * MeSH
• Cell Proliferation MeSH
• Mammals metabolism   MeSH
• Trypanosoma cruzi * genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dasatinib MeSH
• eIF-2 Kinase MeSH

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR-ABL oncogene. Despite the high performance of treatment with tyrosine kinase inhibitors (TKI), about 30% of patients develop resistance to the therapy. To improve the outcomes, identification of new targets of treatment is needed. Here, we explored the Casein Kinase 2 (CK2) as a potential target for CML therapy. Previously, we detected increased phosphorylation of HSP90β Serine 226 in patients non-responding to TKIs imatinib and dasatinib. This site is known to be phosphorylated by CK2, which was also linked to CML resistance to imatinib. In the present work, we established six novel imatinib- and dasatinib-resistant CML cell lines, all of which had increased CK2 activation. A CK2 inhibitor, CX-4945, induced cell death of CML cells in both parental and resistant cell lines. In some cases, CK2 inhibition also potentiated the effects of TKI on the cell metabolic activity. No effects of CK2 inhibition were observed in normal mononuclear blood cells from healthy donors and BCR-ABL negative HL60 cell line. Our data indicate that CK2 kinase supports CML cell viability even in cells with different mechanisms of resistance to TKI, and thus represents a potential target for treatment.

• MeSH
• Apoptosis MeSH
• Fusion Proteins, bcr-abl metabolism   MeSH
• Cell Death MeSH
• Drug Resistance, Neoplasm MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   MeSH
• Dasatinib pharmacology   MeSH
• Imatinib Mesylate pharmacology   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Tyrosine Kinase Inhibitors MeSH
• Casein Kinase II * MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fusion Proteins, bcr-abl MeSH
• Dasatinib MeSH
• Imatinib Mesylate MeSH
• Protein Kinase Inhibitors MeSH
• Tyrosine Kinase Inhibitors MeSH
• Casein Kinase II * MeSH

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

• MeSH
• Dasatinib MeSH
• Endothelial Cells * metabolism   MeSH
• Phosphorylation MeSH
• Humans MeSH
• Neutrophils metabolism   MeSH
• src-Family Kinases * genetics   metabolism   MeSH
• Vasculitis * genetics   MeSH
• Inflammation metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Dasatinib MeSH
• lyn protein-tyrosine kinase MeSH Browser
• src-Family Kinases * MeSH

The treatment outcome in patients with chronic myeloid leukaemia (CML) in blast crisis (BC) is unsatisfactory despite the use of allogeneic stem cell transplantation (ASCT). Moreover, in some patients ASCT is contraindicated, with limited treatment options. We report the case series of two patients with lymphoid BC CML in whom ASCT was not approachable. The first patient developed BC two months after diagnosis in association with dic(7;9)(p11.2;p11.2) and T315I mutation. Blast crisis with central nervous system leukemic involvement and K611N mutation of the SETD2 gene developed abruptly in the second patient five years after ceasing treatment with nilotinib in major molecular response (MMR) at the patient's request. Both underwent one course of chemotherapy in combination with rituximab and imatinib, followed by dasatinib and interferon α (INFα) treatment in the first and dasatinib alone in the second case. Deep molecular response (DMR; MR 4.0) was achieved within a short time in both cases. It is probable that DMR was caused by a specific immune response to CML cells, described in both agents. The challenging medical condition that prompted these case series, and the subsequent results, suggest a re-visit to the use of a combination of well-known drugs as an area for further investigation.

• Keywords
• blast crisis, chronic myeloid leukaemia, interferon alpha, tyrosine kinase inhibitor,
• MeSH
• Blast Crisis * drug therapy   genetics   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   genetics   MeSH
• Dasatinib therapeutic use   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Interferon-alpha therapeutic use   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Dasatinib MeSH
• Protein Kinase Inhibitors MeSH
• Interferon-alpha MeSH

Bcr-Abl tyrosine kinase inhibitors significantly improved Philadelphia chromosome-positive leukaemia therapy. Apart from Bcr-Abl kinase, imatinib, dasatinib, nilotinib, bosutinib and ponatinib are known to have additional off-target effects that might contribute to their antitumoural activities. In our study, we identified aldo-keto reductase 1B10 (AKR1B10) as a novel target for dasatinib. The enzyme AKR1B10 is upregulated in several cancers and influences the metabolism of chemotherapy drugs, including anthracyclines. AKR1B10 reduces anthracyclines to alcohol metabolites that show less antineoplastic properties and tend to accumulate in cardiac tissue. In our experiments, clinically achievable concentrations of dasatinib selectively inhibited AKR1B10 both in experiments with recombinant enzyme (Ki = 0.6 µM) and in a cellular model (IC50 = 0.5 µM). Subsequently, the ability of dasatinib to attenuate AKR1B10-mediated daunorubicin (Daun) resistance was determined in AKR1B10-overexpressing cells. We have demonstrated that dasatinib can synergize with Daun in human cancer cells and enhance its therapeutic effectiveness. Taken together, our results provide new information on how dasatinib may act beyond targeting Bcr-Abl kinase, which may help to design new chemotherapy regimens, including those with anthracyclines.

• Keywords
• Anthracyclines, Cancer therapy, Leukaemia, Multidrug resistance, Reductase,
• MeSH
• Aldo-Keto Reductases antagonists & inhibitors   chemistry   metabolism   MeSH
• Fusion Proteins, bcr-abl antagonists & inhibitors   chemistry   metabolism   MeSH
• A549 Cells MeSH
• Drug Resistance, Neoplasm drug effects   physiology   MeSH
• Dasatinib administration & dosage   MeSH
• Daunorubicin administration & dosage   MeSH
• HCT116 Cells MeSH
• Protein Kinase Inhibitors administration & dosage   MeSH
• Drug Delivery Systems methods   MeSH
• Humans MeSH
• Antineoplastic Agents administration & dosage   MeSH
• Protein Structure, Secondary MeSH
• Molecular Docking Simulation MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• AKR1B10 protein, human MeSH Browser
• Aldo-Keto Reductases MeSH
• Fusion Proteins, bcr-abl MeSH
• Dasatinib MeSH
• Daunorubicin MeSH
• Protein Kinase Inhibitors MeSH
• Antineoplastic Agents MeSH

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. METHODS: Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. RESULTS: Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. CONCLUSIONS: In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC. Video Abstract.

• Keywords
• Cancer, Inflammation, Liver diseases, Obesity, Senolytics,
• MeSH
• Dasatinib adverse effects   MeSH
• Diet, High-Fat MeSH
• Diethylnitrosamine MeSH
• Senotherapeutics adverse effects   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease blood   genetics   pathology   MeSH
• Liver Diseases blood   genetics   pathology   MeSH
• Obesity blood   genetics   pathology   MeSH
• Disease Progression * MeSH
• Quercetin adverse effects   MeSH
• Gene Expression Regulation MeSH
• Aging genetics   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dasatinib MeSH
• Diethylnitrosamine MeSH
• Senotherapeutics MeSH
• Quercetin MeSH

To evaluate long-term real-life results of dasatinib therapy among chronic phase chronic myeloid leukemia patients resistant or intolerant to imatinib, we retrospectively analyzed data of 118 patients treated in centers participating in the database INFINITY. With median follow-up of 37 months, estimated 5-year cumulative incidences of complete cytogenetic and major molecular responses were 78% and 68%, respectively. The estimated 5-year probability of overall survival (OS) and event-free survival (EFS) were 86% and 83%, respectively. Both OS and EFS were significantly improved among patients with BCR-ABL1 transcript level ≤10% at 3 months. Dasatinib toxicity was tolerable however persistent in almost half our patients, even after years of therapy. Pleural effusion occurred in 29% of patients and was responsible for 30% of dasatinib discontinuations. Our results confirmed very good efficacy and acceptable toxicity of dasatinib in second line setting and support the evidence and importance of high-quality real-life CML patient management.

• Keywords
• Chronic myeloid leukemia, chronic phase, daily clinical practice, dasatinib, imatinib, second line,
• MeSH
• Leukemia, Myeloid, Chronic-Phase * drug therapy   genetics   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   genetics   MeSH
• Dasatinib adverse effects   MeSH
• Imatinib Mesylate adverse effects   MeSH
• Protein Kinase Inhibitors adverse effects   MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dasatinib MeSH
• Imatinib Mesylate MeSH
• Protein Kinase Inhibitors MeSH