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The European Respiratory Journal Oct 2020Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib,... (Review)
Review
Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.
Topics: Antineoplastic Agents; Dasatinib; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors
PubMed: 32527740
DOI: 10.1183/13993003.00279-2020 -
International Journal of Hematology May 2021The advent of tyrosine kinase inhibitors (TKIs) has dramatically improved the outcome of patients with chronic myeloid leukemia (CML). Currently, four TKIs are available... (Review)
Review
The advent of tyrosine kinase inhibitors (TKIs) has dramatically improved the outcome of patients with chronic myeloid leukemia (CML). Currently, four TKIs are available for the frontline treatment, including the first-generation TKI (imatinib) and the second-generation TKIs (dasatinib, nilotinib, and bosutinib). The second-generation TKIs lead to a faster and deeper molecular response without a survival benefit compared with imatinib. However, the opportunity for the treatment discontinuation and functional cure requires the achievement of durable deep molecular remission. Therefore, the second-generation TKIs should be considered as initial therapy for chronic-phase CML. Switch of therapy is warranted in case of treatment failure, including resistance and/or intolerance. The life expectancy of patients with CML is approaching that of the general population. Given an expected lifespan, future perspectives should consider the strategy for the optimal choice of TKIs, allowing for long-duration of effective TKI therapy with less toxicity to aim for a functional cure. A novel prediction approach such as artificial intelligence-driven analysis on the accumulated data from clinical trials paves a promising path for the personalized recommendation on frontline TKIs and precise survival prediction.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Artificial Intelligence; Dasatinib; Disease Management; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nitriles; Protein Kinase Inhibitors; Pyrimidines; Quinolines; Stem Cell Transplantation; Transplantation, Homologous
PubMed: 33782818
DOI: 10.1007/s12185-021-03127-5 -
British Journal of Cancer Oct 2023Therapeutic modalities including chemo, radiation, immunotherapy, etc. induce PD-L1 expression that facilitates the adaptive immune resistance to evade the antitumour...
BACKGROUND
Therapeutic modalities including chemo, radiation, immunotherapy, etc. induce PD-L1 expression that facilitates the adaptive immune resistance to evade the antitumour immune response. IFN-γ and hypoxia are some of the crucial inducers of PD-L1 expression in tumour and systemic microenvironment which regulate the expression of PD-L1 via various factors including HIF-1α and MAPK signalling. Hence, inhibition of these factors is crucial to regulate the induced PD-L1 expression and to achieve a durable therapeutic outcome by averting the immunosuppression.
METHODS
B16-F10 melanoma, 4T1 breast carcinoma, and GL261 glioblastoma murine models were established to investigate the in vivo antitumour efficacy of Ponatinib. Western blot, immunohistochemistry, and ELISA were performed to determine the effect of Ponatinib on the immunomodulation of tumour microenvironment (TME). CTL assay and flow cytometry were such as p-MAPK, p-JNK, p-Erk, and cleaved caspase-3 carried out to evaluate the systemic immunity induced by Ponatinib. RNA sequencing, immunofluorescence and Western blot analysis were used to determine the mechanism of PD-L1 regulation by Ponatinib. Antitumour immunity induced by Ponatinib were compared with Dasatinib.
RESULTS
Here, Ponatinib treatment delayed the growth of tumours by inhibiting PD-L1 and modulating TME. It also downregulated the level of PD-L1 downstream signalling molecules. Ponatinib enhanced the CD8 T cell infiltration, regulated Th1/Th2 ratio and depleted tumour associated macrophages (TAMs) in TME. It induced a favourable systemic antitumour immunity by enhancing CD8 T cell population, tumour specific CTL activity, balancing the Th1/Th2 ratio and lowering PD-L1 expression. Ponatinib inhibited FoxP3 expression in tumour and spleen. RNA sequencing data revealed that Ponatinib treatment downregulated the genes related to transcription including HIF-1α. Further mechanistic studies showed that it inhibited the IFN-γ and hypoxia induced PD-L1 expression via regulating HIF-1α. Dasatinib was used as control to prove that Ponatinib induced antitumour immunity is via PD-L1 inhibition mediated T cell activation.
CONCLUSIONS
RNA sequencing data along with rigorous in vitro and in vivo studies revealed a novel molecular mechanism by which Ponatinib can inhibit the induced PD-L1 levels via regulating HIF-1α expression which leads to modulation of tumour microenvironment. Thus, our study provides a novel therapeutic insight of Ponatinib for the treatment of solid tumours where it can be used alone or in combination with other drugs which are known to induce PD-L1 expression and generate adaptive resistance.
Topics: Humans; Animals; Mice; B7-H1 Antigen; Tumor Microenvironment; Dasatinib; Neoplasms; Immunosuppressive Agents; Hypoxia; Cell Line, Tumor
PubMed: 37400678
DOI: 10.1038/s41416-023-02316-9 -
Scandinavian Journal of Gastroenterology Apr 2022Dasatinib, a second-generation tyrosine kinase inhibitor, is widely used in patients with haematological malignancies. The main side effects of dasatinib are...
BACKGROUND
Dasatinib, a second-generation tyrosine kinase inhibitor, is widely used in patients with haematological malignancies. The main side effects of dasatinib are myelosuppression and pleural effusion; however, colitis, such as haemorrhagic colitis and cytomegalovirus (CMV) colitis, have been reported as rare side effects. There are only a few studies conducted on dasatinib-induced colitis.
AIMS
This study aimed to clarify the clinical, endoscopic and pathological features of dasatinib-induced colitis.
METHODS
This retrospective study included 51 consecutive patients who received dasatinib therapy between June 2009 and July 2020. Dasatinib-induced colitis was defined as the presence of colitis symptoms, exclusion of other diseases that could cause colitis, and improvement in symptoms after dasatinib withdrawal or dose reduction. CMV positivity was determined based on the positive result of CMV immunostaining.
RESULTS
Dasatinib-induced colitis was diagnosed in nine of 51 patients (17.6%), and most of the symptoms were mild diarrhoea and bloody stools. The endoscopic findings were characterised by loss of vascular pattern (100%) and multiple small erosions (83.3%) which were mainly found in the transverse and descending colon. In a patient who underwent follow-up colonoscopy once a year while taking dasatinib, endoscopic findings changed from initial erythematous spots to multiple erosions, and finally to multiple small round elevations with erosion on the top that disappeared after discontinuation of dasatinib. Anti-CMV therapy was administered to one patient, but the treatment failed. All patients with dasatinib-induced colitis were cured after the discontinuation of dasatinib.
CONCLUSION
Physicians should consider CMV reactivation to manage dasatinib-induced colitis.
Topics: Colitis; Colonoscopy; Cytomegalovirus Infections; Dasatinib; Enterocolitis; Gastrointestinal Hemorrhage; Humans; Retrospective Studies
PubMed: 34978242
DOI: 10.1080/00365521.2021.2022190 -
Blood Jun 2023
Topics: Humans; Dasatinib; 14-3-3 Proteins; Pyrimidines; Hemorrhage; Inflammation
PubMed: 37318908
DOI: 10.1182/blood.2023020399 -
Journal For Immunotherapy of Cancer Oct 2023Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years....
Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring.
Topics: Animals; Humans; Mice; Dasatinib; Histocompatibility Antigens Class II; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 37793852
DOI: 10.1136/jitc-2022-006619 -
Blood Advances Jun 2023The tyrosine kinase inhibitor dasatinib is approved for Philadelphia chromosome-positive leukemia, including chronic myeloid leukemia (CML). Although effective and well...
The tyrosine kinase inhibitor dasatinib is approved for Philadelphia chromosome-positive leukemia, including chronic myeloid leukemia (CML). Although effective and well tolerated, patients typically exhibit a transient lymphocytosis after dasatinib uptake. To date, the underlying physiological process linking dasatinib to lymphocytosis remains unknown. Here, we used a small rodent model to examine the mechanism of dasatinib-induced lymphocytosis, focusing on lymphocyte trafficking into and out of secondary lymphoid organs. Our data indicate that lymphocyte homing to lymph nodes and spleen remained unaffected by dasatinib treatment. In contrast, dasatinib promoted lymphocyte egress from spleen with kinetics consistent with the observed lymphocytosis. Unexpectedly, dasatinib-induced lymphocyte egress occurred independently of canonical sphingosine-1-phosphate-mediated egress signals; instead, dasatinib treatment led to a decrease in spleen size, concomitant with increased splenic stromal cell contractility, as measured by myosin light chain phosphorylation. Accordingly, dasatinib-induced lymphocytosis was partially reversed by pharmacological inhibition of the contraction-promoting factor Rho-rho associated kinase. Finally, we uncovered a decrease in spleen size in patients with CML who showed lymphocytosis immediately after dasatinib treatment, and this reduction was proportional to the magnitude of lymphocytosis and dasatinib plasma levels. In summary, our work provides evidence that dasatinib-induced lymphocytosis is a consequence of drug-induced contractility of splenic stromal cells.
Topics: Humans; Dasatinib; Lymphocytosis; Spleen; Pyrimidines; Thiazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 36583674
DOI: 10.1182/bloodadvances.2022009279 -
Molecular Metabolism Oct 2022Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been...
OBJECTIVE
Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes.
METHODS
Using fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed.
RESULTS
Results showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes.
CONCLUSION
Our findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin.
Topics: Animals; Cellular Senescence; Dasatinib; Doxorubicin; Hepatocytes; Humans; Insulin; Insulin Resistance; Mice; Quercetin; Receptor, Insulin
PubMed: 35872305
DOI: 10.1016/j.molmet.2022.101558 -
Cells May 2023Thyroid cancer is the most common endocrine neoplasm, and despite its overall high survival rate, patients with metastatic disease or tumors that resist radioactive...
Thyroid cancer is the most common endocrine neoplasm, and despite its overall high survival rate, patients with metastatic disease or tumors that resist radioactive iodine experience a significantly worse prognosis. Helping these patients requires a better understanding of how therapeutics alter cellular function. Here, we describe the change in metabolite profiles after treating thyroid cancer cells with the kinase inhibitors dasatinib and trametinib. We reveal alterations to glycolysis, the TCA cycle, and amino acid levels. We also highlight how these drugs promote short-term accumulation of the tumor-suppressive metabolite 2-oxoglutarate, and demonstrate that it reduces the viability of thyroid cancer cells in vitro. These results show that kinase inhibition profoundly alters the metabolome of cancer cells and highlight the need to better understand how therapeutics reprogram metabolic processes, and ultimately, cancer cell behavior.
Topics: Humans; Dasatinib; src-Family Kinases; Iodine Radioisotopes; Protein Kinase Inhibitors; Thyroid Neoplasms; Cell Line, Tumor
PubMed: 37408209
DOI: 10.3390/cells12101374 -
Acta Dermato-venereologica Apr 2023Keloids are skin tumours caused by aberrant growth of dermal fibroblasts. Cellular senescence contributes to aging and various pathological conditions, including cancer,...
Keloids are skin tumours caused by aberrant growth of dermal fibroblasts. Cellular senescence contributes to aging and various pathological conditions, including cancer, atherosclerosis, and fibrotic diseases. However, the effects of cellular senescence and senolytic drugs on keloids remain largely unknown. This study investigated senescent fibroblasts in keloids and assessed the effects of dasatinib on these cells. Tissues acquired from keloid removal surgery were analysed for senescence-associated β-galactosidase-positive cells, p16 expression, and the effects of dasatinib treatment on keloids. Keloid tissue was xenotransplanted into mice, and the effect of intralesional dasatinib injection on keloid growth was observed. The results showed that the numbers of β-galactosidase-positive and p16-expressing cells were higher in the keloids compared with in the controls. Dasatinib induced selective clearance of senescent cells and decreased procollagen expression in cultured keloid fibroblasts. In this xenotransplant keloid mouse model, intralesional injection of dasatinib reduced gross keloid tissue weight and the expression of both procollagen and p16. In addition, dasatinib-treated keloid fibroblasts conditioned medium reduced procollagen and p16 expression in cultured keloid fibroblasts. In conclusion, these results suggest that an increased number of senescent fibroblasts may play an important role in the pathogenesis of keloids. Therefore, dasatinib could be an alternative treatment for patients with keloids.
Topics: Animals; Mice; Keloid; Procollagen; Dasatinib; Cellular Senescence; Fibroblasts; Cells, Cultured
PubMed: 37021598
DOI: 10.2340/actadv.v103.4475