Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.
- MeSH
- antitumorózní látky * škodlivé účinky MeSH
- chronická myeloidní leukemie * farmakoterapie genetika MeSH
- imatinib mesylát terapeutické užití MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- membránové transportní proteiny terapeutické užití MeSH
- prognóza MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recent studies have underscored the importance of gamma-delta (γδ) T cells in mediating potent MHC-unrestricted cytotoxicity in numerous malignancies. Here, we analyzed Vδ1 and Vδ2 γδ T cell subsets in newly diagnosed chronic myeloid leukemia (CML) patients (n = 40) who had initiated tyrosine kinase inhibitor (TKI) therapy including imatinib (n = 22), nilotinib (n = 14) and dasatinib (n = 4). Patient peripheral blood samples were analyzed at diagnosis and monitored prospectively at 3, 6, 12 and 18 months post-TKI. γδ T cells isolated from healthy donors and CML patients were used against K562, LAMA-84 and KYO-1 cell lines and against primary CML cells in cytotoxicity assays. We found large expansions of Vδ1 and Vδ2 T cells in patients at diagnosis compared to age-matched healthy donors (n = 40) (p < 0.0001). The γδ T cell reconstitution in patients on imatinib and also on nilotinib showed significant reductions of Vδ1 T cell and Vδ2 T cell absolute counts at 3 months compared to diagnosis. Importantly, Vδ1 and Vδ2 T absolute cell counts remained at normal levels from 3 months throughout the follow-up. Next, we observed susceptibility to specific lysis of primary CML tumor cells by Vδ1 T cells from healthy donors. Furthermore, we determined inherent cytotoxic reactivity by autologous patients' Vδ1 T lymphocytes against primary CML tumor cells. Finally, the TCR clonality profiles showed in CML patients mostly polyclonal repertoires regardless of the TKI. Our results provide further evidence into γδ T cell antileukemia immunity in CML that might be beneficial for long-term disease control and treatment outcome.
- MeSH
- buněčné linie MeSH
- chronická myeloidní leukemie * farmakoterapie metabolismus MeSH
- imatinib mesylát farmakologie terapeutické užití MeSH
- lidé MeSH
- myeloidní leukemie * metabolismus MeSH
- receptory antigenů T-buněk gama-delta metabolismus MeSH
- T-lymfocyty - podskupiny MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The clinical presentation of chronic myeloid leukemia (CML) at diagnosis differs in children compared to adults. At younger age, anemia appears to be frequent at diagnosis, but its prevalence and its impact on prognosis are not well known. In the International Registry of Childhood CML, we selected children and adolescents in chronic phase at diagnosis of CML and treated upfront with imatinib. We examined their hemoglobin level at diagnosis according to the WHO grades to assess the prevalence of anemia and its impact on response to tyrosine kinase inhibitors (TKIs). Data on 430 patients were included. Anemia at diagnosis was observed in 350 patients (81%), with a mean hemoglobin level of 96.4 g/l (SD 23.6). Among them, 182 patients (52%) presented with moderate anemia and 110 (31%) with severe anemia while 58 (17%) had mild anemia. Compared with mild and no anemia, moderate and severe forms were significantly associated with younger age at diagnosis, asthenia, splenomegaly, and increased leukocyte and basophil counts. Delays in achieving major and deep molecular responses were significantly increased for patients with moderate and severe anemia, and also failure of imatinib treatment was more frequent in these two sub-cohorts. However, hemoglobin level was not significantly associated with survival. Anemia at diagnosis of pediatric CML was frequent and may be considered as a prognostic factor.
- MeSH
- anemie * farmakoterapie MeSH
- antitumorózní látky * terapeutické užití MeSH
- chronická myeloidní leukemie * farmakoterapie MeSH
- dítě MeSH
- dospělí MeSH
- hemoglobiny MeSH
- imatinib mesylát terapeutické užití MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- mladiství MeSH
- prevalence MeSH
- prognóza MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- nilotinib, bosutinib, ponatinib,
- MeSH
- aniliny aplikace a dávkování terapeutické užití MeSH
- chinoliny aplikace a dávkování terapeutické užití MeSH
- chronická fáze myeloidní leukemie terapie MeSH
- chronická myeloidní leukemie * terapie MeSH
- dasatinib aplikace a dávkování terapeutické užití MeSH
- imatinib mesylát aplikace a dávkování terapeutické užití MeSH
- imidazoly aplikace a dávkování terapeutické užití MeSH
- inhibitory proteinkinas aplikace a dávkování terapeutické užití MeSH
- inhibitory tyrosinkinasy aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- nemoc štěpu proti hostiteli MeSH
- nitrily aplikace a dávkování terapeutické užití MeSH
- pyridaziny aplikace a dávkování terapeutické užití MeSH
- pyrimidiny aplikace a dávkování terapeutické užití MeSH
- retrospektivní studie MeSH
- transplantace hematopoetických kmenových buněk metody MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- asciminib,
- MeSH
- chronická myeloidní leukemie * farmakoterapie MeSH
- diabetes mellitus etiologie MeSH
- hydroxymočovina aplikace a dávkování škodlivé účinky MeSH
- imatinib mesylát aplikace a dávkování terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- tyrosinkinasy * aplikace a dávkování škodlivé účinky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The lysosomal sequestration of hydrophobic weak-base anticancer drugs is one proposed mechanism for the reduced availability of these drugs at target sites, resulting in a marked decrease in cytotoxicity and consequent resistance. While this subject is receiving increasing emphasis, it is so far only in laboratory experiments. Imatinib is a targeted anticancer drug used to treat chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GISTs), and a number of other malignancies. Its physicochemical properties make it a typical hydrophobic weak-base drug that accumulates in the lysosomes of tumour cells. Further laboratory studies suggest that this might significantly reduce its antitumor efficacy. However, a detailed analysis of published laboratory studies shows that lysosomal accumulation cannot be considered a clearly proven mechanism of resistance to imatinib. Second, more than 20 years of clinical experience with imatinib has revealed a number of resistance mechanisms, none of which is related to its accumulation in lysosomes. This review focuses on the analysis of salient evidence and raises a fundamental question about the significance of lysosomal sequestration of weak-base drugs in general as a possible resistance mechanism both in clinical and laboratory settings.
Chronic myeloid leukemia (CML) is a malignant hematopoietic disorder distinguished by the presence of a BCR‑ABL1 fused oncogene with constitutive kinase activity. Targeted CML therapy by specific tyrosine kinase inhibitors (TKIs) leads to a marked improvement in the survival of the patients and their quality of life. However, the development of resistance to TKIs remains a critical issue for a subset of patients. The most common cause of resistance are numerous point mutations in the BCR‑ABL1 gene, followed by less common mutations and multiple mutation-independent mechanisms. Recently, exosomes, which are extracellular vesicles excreted from normal and tumor cells, have been associated with drug resistance and cancer progression. The aim of the present study was to characterize the exosomes released by imatinib‑resistant K562 (K562IR) cells. The K562IR‑derived exosomes were internalized by imatinib‑sensitive K562 cells, which thereby increased their survival in the presence of 2 µM imatinib. The exosomal cargo was subsequently analyzed to identify resistance‑associated markers using a deep label‑free quantification proteomic analysis. There were >3,000 exosomal proteins identified of which, 35 were found to be differentially expressed. From this, a total of 3, namely the membrane proteins, interferon‑induced transmembrane protein 3, CD146 and CD36, were markedly upregulated in the exosomes derived from the K562IR cells, and exhibited surface localization. The upregulation of these proteins was verified in the K562IR exosomes, and also in the K562IR cells. Using flow cytometric analysis, it was possible to further demonstrate the potential of CD146 as a cell surface marker associated with imatinib resistance in K562 cells. Taken together, these results suggested that exosomes and their respective candidate surface proteins could be potential diagnostic markers of TKI drug resistance in CML therapy.
- MeSH
- antigen CD146 metabolismus MeSH
- antigeny CD36 metabolismus MeSH
- apoptóza účinky léků MeSH
- bcr-abl fúzové proteiny antagonisté a inhibitory genetika MeSH
- buňky K562 MeSH
- chemorezistence MeSH
- chronická myeloidní leukemie farmakoterapie genetika patologie MeSH
- exozómy účinky léků metabolismus MeSH
- imatinib mesylát farmakologie terapeutické užití MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- lidé MeSH
- membránové proteiny metabolismus MeSH
- nádorové buněčné linie MeSH
- proteiny vázající RNA metabolismus MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Pokroky v molekulární klasifikaci gastrointestinálního stromálního nádoru (GIST), zejména jeho subklasifikace podle zjištěných genetických alterací i vývoj nových léků v posledních dvou letech výrazným způsobem ovlinily volbu léčebných postupů jak v časné fázi nemoci, tak i vedení léčby paliativní.
The advances in molecular biology of gastrointestinal stromal tumors (GIST) in recent years has allowed to distinguish various tumor subtypes that respond differently to anticancer therapy. This fact together with the development of new active drugs has led to the changes in standards of care in both adjuvant and palliative settings.
- Klíčová slova
- avapritinib, ripretinib, pazopanib, regorafenib,
- MeSH
- adjuvantní chemoterapie metody MeSH
- antitumorózní látky terapeutické užití MeSH
- gastrointestinální stromální tumory * diagnóza farmakoterapie genetika klasifikace MeSH
- imatinib mesylát terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
Lysosomal sequestration of weak base drugs has been identified as one of the stress-related mechanisms that trigger in vitro lysosomal biogenesis controlled by transcription factor EB (TFEB). Whether such mechanism can induce lysosomal biogenesis in vivo is unknown. In this study, we addressed the question whether prolonged treatment with sunitinib (SUN) in patients with advanced renal cell carcinoma (n = 22) and with imatinib (IM) in those with gastrointestinal stromal tumor (n = 6) could induce lysosomal biogenesis in leukocytes. Lysosomal biogenesis was monitored using immunoblotting of three lysosomal membrane proteins: lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2) and vacuolar H+-ATPase, B2 subunit (ATP6V1B2). Present results indicate that prolonged treatment with SUN affects LAMP1 and LAMP2 expression only marginally in most patients. In contrast, changes in ATP6V1B2 expression were marked and resembled irregular oscillations. Very similar changes in the expression of lysosomal membrane proteins were also found in IM-treated patients. Conclusion: prolonged treatment of cancer patients with SUN and IM did not induce leucocyte lysosomal biogenesis but dramatically affected expression of ATP6V1B2.
- MeSH
- gastrointestinální stromální tumory farmakoterapie metabolismus MeSH
- imatinib mesylát terapeutické užití MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- karcinom z renálních buněk farmakoterapie metabolismus MeSH
- leukocyty metabolismus MeSH
- lidé MeSH
- lyzozomy metabolismus MeSH
- membránové glykoproteiny asociované s lyzozomy metabolismus MeSH
- sunitinib terapeutické užití MeSH
- transkripční faktory BHLH-Zip metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
V indikaci metastatického GIST zůstávají standardem preparáty imatinib, sunitinib, regorafenib. Avapritinib (nový TK-inhibitor) je nově schválen v indikaci 1. linie metastatického GIST s mutací PDGFR D842, ale neprokázal superioritu oproti regorafenibu v celé populace GIST. Mezi další zajímavé tyrosinkinázové inhibitory patří kabozantinib, pazopanib, ripretinib. Data o efektivitě BRAF blokátorů a imunoterapii anti-PD-1 preparáty jsou zatím velmi omezená. Znovunasazení imatinibu po selhání předchozí léčby imatunibem, sunitinibem a regorafenibem se zdá být efektní jen minimálně. Doporučený standard 3leté adjuvantní léčby imatinibemu pacientů po resekci GIST vysokého rizika nezměnily ani výsledky studie PERSIST s aplikovaným imatinibem v adjuvantní indikaci po dobu 5 let.
Imatinib, sunitinib, and regorafenib have remained the standard therapy for metastatic GIST. Avapritinib (a novel TK inhibitor) has been newly approved as the first-line treatment of metastatic GIST with a PDGFR D842 mutation, but has not been shown to be superior compared with regorafenib in the entire GIST population. Other interesting tyrosine kinase inhibitors include cabozantinib, pazopanib, and ripretinib. Data on the efficacy of BRAF inhibitors and immunotherapy with anti-PD-1 drugs have been limited so far. Repeated administration of imatinib after failure of previous treatment with imatinib, sunitinib, and regorafenib appears to have a minimum effect only. The recommended standard of 3-year adjuvant therapy with imatinib in patients after high-risk GIST resection has remained unchanged by the results of the PERSIST clinical trial with a 5-year administration of adjuvant imatinib.
- Klíčová slova
- regorafenib, cabozantinib, avapritinib, ripretinib,
- MeSH
- anilidy aplikace a dávkování terapeutické užití MeSH
- antitumorózní látky MeSH
- fenylmočovinové sloučeniny aplikace a dávkování terapeutické užití MeSH
- gastrointestinální stromální tumory * terapie MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- imatinib mesylát aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- močovina analogy a deriváty MeSH
- naftyridiny aplikace a dávkování terapeutické užití MeSH
- pyrazoly aplikace a dávkování terapeutické užití MeSH
- pyridiny aplikace a dávkování terapeutické užití MeSH
- pyrroly aplikace a dávkování terapeutické užití MeSH
- sunitinib aplikace a dávkování terapeutické užití MeSH
- triaziny aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
