abl tyrosine kinase
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2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Shohei Kawakami ◽  
Mitsuyo Tsuma-Kaneko ◽  
Masakazu Sawanobori ◽  
Tomoko Uno ◽  
Yoshihiko Nakamura ◽  
...  

AbstractIn this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation. In BCR/ABL+ leukemic cells, pterostilbene decreased the BCR/ABL fusion protein levels and suppressed AKT and NF-κB activation. We further demonstrated that pterostilbene along with U0126, an inhibitor of the MEK/ERK signaling pathway, synergistically induced apoptosis of BCR/ABL+ cells. Our results further suggest that pterostilbene-promoted downregulation of BCR/ABL involves caspase activation triggered by proteasome inhibition-induced endoplasmic reticulum stress. Moreover, oral administration of pterostilbene significantly suppressed tumor growth in mice transplanted with BCR/ABL+ leukemic cells. Taken together, these results suggest that pterostilbene may hold potential for the treatment of BCR/ABL+ leukemia, in particular for those showing ABL-dependent TKI resistance.


2021 ◽  
pp. 1-10
Author(s):  
Seiichi Okabe ◽  
Yuko Tanaka ◽  
Akihiko Gotoh

BACKGROUND: Although Abelson (ABL) tyrosine kinase inhibitors (TKIs) have demonstrated potency against chronic myeloid leukemia (CML), resistance to ABL TKIs can develop in CML patients after discontinuation of therapy. OBJECTIVE: Glucose metabolism may be altered in CML cells because glucose is a key metabolite used by tumor cells. We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. METHODS: We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. RESULTS: Treatment with D-mannose for 72 h inhibited the growth of K562 cells. Combined treatment using ABL TKIs and D-mannose induced a significantly higher level of cytotoxicity in Philadelphia chromosome (Ph)-positive leukemia cells than in control cells. In the mouse model, severe toxicity was observed as evidenced by body weight loss in the ponatinib and D-mannose combination treatment groups. CONCLUSION: Our results indicate that metabolic reprogramming may be a useful strategy against Ph-positive leukemia cells. However, caution should be exercised during clinical applications.


2021 ◽  
Vol 13 (2) ◽  
pp. 73-76
Author(s):  
Sungjoon Yoon ◽  
Seon Deuk Kim ◽  
Juhee Lee ◽  
Mu Seong Kim ◽  
Yong Woo Shin ◽  
...  

Nilotinib is a Bcr-Abl tyrosine kinase inhibitor used to treat chronic myelogenous leukemia. There have been case reports of nilotinib-related vasculopathy. However, most cases present peripheral artery disease, whilst reports of nilotinib-related cerebrovascular disease are quite uncommon. Herein, we report a case of nilotinib-induced intracranial stenosis in a patient with recurrent transient ischemic attacks and discuss the results of serial vessel wall magnetic resonance imaging.


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A345-A346
Author(s):  
Sean Tracy ◽  
Hrishi Venkatesh ◽  
Lynn Heltemes-Harris ◽  
Gregory Hubbard ◽  
Can Hekim ◽  
...  

BackgroundPhenotypic exhaustion of CD4+ T-cells is a strong negative prognostic factor in acute lymphoblastic leukemia (ALL).1–3 Despite this, PD1/PD-L1 immune checkpoint therapy has shown little activity in this disease setting to date. Factors influencing the responsiveness of the T-cell compartment to checkpoint blockade are unknown.MethodsAn established murine model of BCR-ABL+ ALL was used. Leukemia was established by tail vein injection, and mice were treated with the BCR-ABL tyrosine kinase inhibitor nilotinib with or without PD-L1 mAb therapy. scRNAseq/TCRseq was performed using multiple treatment groups.ResultsTreatment of leukemia-bearing mice with a combination of the BCR-ABL tyrosine kinase inhibitor nilotinib and PD-L1 immune checkpoint blockade led to eradication of leukemia in 70% of treated mice (figure 1). Efficacy was dependent on the presence of CD4+ T-cells, while CD8+ T-cells appeared to play a lesser role. Direct cytotoxicity by CD4+ T-cells was confirmed in live cell-killing assays (figure 2). Mice that were treated with PD-L1 blockade and survived to day 100 were found to have no detectable residual leukemia. They were also protected from leukemia rechallenge, suggesting the elicitation of a memory response. scRNAseq analysis revealed that CD44hi CD4+ T-cells were highly heterogeneous, with regulatory, effector, and stem-like TCF7+ precursor subsets present (figures 3–4). A unique population of CD4+ T-cells was elicited by live leukemia challenge (clusters 6 and 7 in figure 3) but not by vaccination with heat-killed leukemia cells. This subset was characterized by relatively low levels of expression of TCF7, but high levels of expression of Granzyme B, TOX, the effector cytokines IFNγ and TNFα, the inhibitory receptors PD1, TIM3, and LAG3, and the chemokine CCL5 (figure 5). PD-L1 checkpoint blockade was associated with early narrowing of the clonality of this population (figure 6), decreased markers of exhaustion, and more robust synthesis of TNFα.Abstract 321 Figure 1Survival analysis. BCR-ABL+ ALL was established by tail vein injection on day 0. Nilotinib (75 mg/kg) was administered via oral gavage. mAbs targeting PD-L1 with or without depleting antibodies towards CD4 or CD8 were administered via intraperitoneal injection. p-value derived by log-rank analysisAbstract 321 Figure 2Analysis of the increase in the number of dead cells (y-axis) over time (x-axis) from a live killing assay (Incucyte) using splenic CD4+ or CD8+ T-cells from experimental arms as treated in figure 3. Control traces from separate wells with LM138 target cells only are included. Experiments were done using Cytotox NIRAbstract 321 Figure 3(Left) Experimental approach. 5 groups (n=4 mice/group) were treated in parallel with the indicated conditions. CD44hi CD4+ T-cells from the spleen and bone marrow of mice in each group were labelled with oligo-conjugated hashtag antibodies (Biolegend) and CITE-SEQ antibodies towards PD1, TIM3, LAG3, CD25, and TIGIT, prior to FACs-sorting. scRNAseq/TCRseq analysis (10x Genomics) was performed on 5,349 individual cells after multiplet removal. (Right) UMAP plots of all cells combined. Clusters were identified by differential expression of canonical gene productsAbstract 321 Figure 4Feature plots demonstrating expression of canonical gene products projected onto the UMAP plot in figure 3. Antibody derived tags (ADTs; bottom row) indicate expression level of surface proteins profiled using CITESEQ antibodiesAbstract 321 Figure 5Heatmap of select gene product expression levels in exhausted (cluster 6) CD4+ T-cells across treatment conditionsAbstract 321 Figure 6Simpsons diversity index of the TCR repertoire across treatment arms. Lower values indicate relatively decreased clonalityConclusionsPDL1 immune checkpoint blockade is effective at eradicating residual disease in preclinical models of BCR-ABL+ ALL. ALL elicits a unique CD4+ memory/effector subset characterized by the potential for both chemotactic and cytotoxic functions. Leukemia induces early exhaustion of this subset, which is countered by PDL1 blockade. Efforts to extend these observations to human specimens are underway and will be reported.ReferencesHohtari H, Brück O, Blom S, et al. Immune cell constitution in bone marrow microenvironment predicts outcome in adult ALL. Leukemia 2019;33(7):1570–1582. Blaeschke F, Willier S, Stenger D, et al. Leukemia-induced dysfunctional TIM-3. Leukemia 2020;34(10):2607–2620.Liu L, Chang YJ, Xu LP, et al. T cell exhaustion characterized by compromised MHC class I and II restricted cytotoxic activity associates with acute B lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. Clin Immunol 2018;190:32–40.


2021 ◽  
Vol 9 (41) ◽  
pp. 54-57
Author(s):  
Dhara Dave ◽  
John Kimbugwe ◽  
Randa Hazam ◽  
Saria Tasnim ◽  
Manish Patel

The BCR-ABL tyrosine kinase inhibitor dasatinib is a potent treatment for chronic myeloid leukemia (CML). However, it is associated with pulmonary toxicities. Commonly reported dasatinib related pulmonary toxicities include pleural effusion, lung parenchymal abnormalities, and pulmonary hypertension. Diffuse alveolar hemorrhage (DAH) during treatment with dasatinib is very rare. To the best of our knowledge there are only two cases reported. Here we report a 57-year-old Caucasian woman who developed acute hypoxic respiratory failure while on dasatinib for treatment of CML. She was diagnosed with DAH suspected to be secondary to dasatinib, after other common etiologies were ruled out. There was full recovery after stopping dasatinib and treatment with corticosteroids. Keywords: Dasatinib, pulmonary toxicity, diffuse alveolar hemorrhage, chronic myeloid leukemia


2021 ◽  
Vol 14 (3) ◽  
pp. 1441-1446
Author(s):  
Zakaria Maat ◽  
Kamran Mushtaq ◽  
Mohamed A. Yassin

Dasatinib is a BCR-ABL tyrosine kinase inhibitor which was approved in 2006 for the treatment of adults diagnosed with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) and accelerated (myeloid or lymphoid blast) phase and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia. Common adverse reactions (>15%) in patients diagnosed with CP-CML include myelosuppression, fluid retention, and diarrhea. We report a 34-year-old Filipino female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for 2 months, which progressed to colitis.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shunsuke Maruta ◽  
Kyohei Usami ◽  
Kazuko Tajiri ◽  
Masafumi Otani ◽  
Daigo Hiraya ◽  
...  

Abstract Background Nilotinib, a second-generation BCR-ABL tyrosine kinase inhibitor (TKI), is highly effective in the treatment of patients with chronic myeloid leukemia (CML), despite being more vasculotoxic than older TKIs such as imatinib. Herein, we present a case of nilotinib-associated vasospastic angina confirmed by an acetylcholine spasm provocation test. Case presentation A 62-year-old CML patient treated with 300 mg nilotinib twice daily complained of several episodes of rest angina and was hospitalized at our institution. Coronary angiography revealed no severe organic stenosis, and the acetylcholine spasm provocation test confirmed the diagnosis of vasospastic angina. Although treatment with a calcium channel blocker and nicorandil reduced the frequency of chest pain, angina symptoms continued to occur. At 10 months post discharge, the patient complained of increased frequency of angina; therefore, the nilotinib dosage was reduced to 150 mg twice daily. Consequently, the patient reported a significant improvement in chest symptoms. Conclusions This case report highlights the potential vasculotoxic effects of nilotinib. Cardiologists and hematologists should be vigilant for coronary artery spasm as a possible vascular adverse event caused by nilotinib.


2021 ◽  
Vol 29 (1-2) ◽  
Author(s):  
Kristine Olsen ◽  
Live Storehagen Dansie ◽  
Irene Litleskare ◽  
Hege Salvesen Blix

Background: Antineoplastic agents (ATC group L01) have not been assigned DDDs due to highly interindividualvariation in dosages. Consumption data has therefore been presented in other measurement units such as grams of active ingredient. However, the protein kinase inhibitors (PKIs) are a rapidly growing drug group that was introduced to the market recently and are administered orally in a fixed dose. DDDs were therefore established for the PKIs in 2020. In this study we aim to assess whether the newly assigned DDDs would better express drug utilisation patterns in Norway than the current units of measurement.Methods: Sales data for PKIs (ATC level L01E) by grams, cost, units and packages for 2019 were collectedfrom the Norwegian Drug Wholesales Statistics and data on number of prescriptions and prevalence for 2019were collected from the Norwegian Prescription Database (NorPD). DDDs were calculated by applying thevalues of the new DDDs.Results: The proportions of the different substances varied according to the unit of measurement. DDDs andpackages had the highest similarity and correlated better than grams with the prevalence of use in theNorwegian population. BCR-ABL tyrosine kinase inhibitors was the largest group accounting for 31% ofthe total consumption (DDD/1000 inhabitants/day) and imatinib was the most sold PKI in all units of measurement except cost.Conclusions: Using an international agreed unit of measurement gives reliability to the study result. Assignment of DDDs to PKIs will improve the quality of drug utilisation studies in this area.


2021 ◽  
Vol 12 (3) ◽  
pp. 3357-3371

The novel coronavirus pandemic (COVID-19) caused by SARS-CoV-2 has affected more than 53 million individuals worldwide. Currently, there is a dire need to develop or find potential drugs that can treat SARS-CoV-2 infection. One of the standard methods to accelerate drug discovery and development in pandemics is to screen currently available medications against the critical therapeutic targets to find potential therapeutic agents. The literature has pointed out the 3CLpro and RdRp proteins as the most important proteins involved in viral replications. In the present study, we used an in-silico modeling approach to examine the affinity of six tyrosine kinases inhibitors (TKIs), Imatinib, Ponatinib, Nilotinib, Gefitinib, Erlotinib, and Dasatinibagainst the 3CLpro and RdRp by calculating the energy balance. The six tested TKIs had more than -7 Kcal/mol energy balance values for both viral target proteins. Nilotinib and Ponatinib showed the highest affinity for 3CLpro (-8.32, -8.16, respectively) while Dasatinib, Ponatinib, and Imatinib presented the strongest binding toRdRp(-14.50, -10.57, -9.46, respectively). Based on these findings, we recommend future evaluations of TKIs for SARs-CoV-2 infection in-vitro and further testing in clinical trials.


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