scholarly journals ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro

2013 ◽  
pp. 63 ◽  
Author(s):  
Karin Skoglund ◽  
Samuel Boiso Moreno ◽  
Maria Baytar ◽  
Jan Ingvar Jönsson ◽  
Henrik Gréen
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors

In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia

2018 ◽  
Vol 82 (5) ◽  
pp. 795-802 ◽  
Author(s):  
Hisham Qosa ◽  
Brittany R. Avaritt ◽  
Neil R. Hartman ◽  
Donna A. Volpe
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Drug Induced

scholarly journals Combating Acquired Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2015 ◽  
pp. e165-e173 ◽  
Author(s):  
Christine M. Lovly
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Initial Response ◽  
In Vitro Models ◽  
Tumor Biopsy

The prospective identification and therapeutic targeting of oncogenic tyrosine kinases with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment for patients with non–small cell lung cancer (NSCLC). TKI therapy frequently induces dramatic clinical responses in molecularly defined cohorts of patients with lung cancer, paving the way for the implementation of precision medicine. Unfortunately, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. This brief review will provide an overview of the complex and heterogeneous problem of acquired resistance to TKI therapy in NSCLC, with a focus on EGFR-mutant and ALK-rearranged NSCLC. In vitro models of TKI resistance and analysis of tumor biopsy samples at the time of disease progression have generated breakthroughs in our understanding of the spectrum of mechanisms by which a tumor can thwart TKI therapy and have provided an important rationale for the development of novel approaches to delay or overcome resistance. Numerous ongoing clinical trials implement strategies, including novel, more potent TKIs and rational combinations of targeted therapies, some of which have already proven effective in surmounting therapeutic resistance.

scholarly journals MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
María Luz Morales ◽  
Alicia Arenas ◽  
Alejandra Ortiz-Ruiz ◽  
Alejandra Leivas ◽  
Inmaculada Rapado ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Resistance Pathway ◽  
Acute Myeloid

AbstractFMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.

A Pathway-focused GSEA Platform In AML That Interrogates Interaction of Flt3ITD and tMLL with Their Epigenetic Targets (p16INK4a, DAPK1, and RUNX3), While Accurately Reporting Broad-based AML Prognosis and Targeting-agent Sensitivity.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1660-1660
Author(s):  
Tareq Al Baghdadi ◽  
Chirayu Goswami ◽  
Hamid Sayar ◽  
Katie J. Sargent ◽  
Larry Cripe ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Hdac Inhibitor ◽  
Kinase Inhibitors ◽  
Normal Karyotype ◽  
Dual Inhibitor ◽  
Expression Levels ◽  
Kaplan Meier

Abstract Abstract 1660 GSEA (gene-set enrichment array) analysis for expression levels in acute myeloid leukemia (AML) blasts of hoxA9/meis1, has afforded additional prognostic capacity to cytogenetically-defined subtypes. Signaling pathway (KEGG, GO, Ingenuity) analysis of Affymetrix gene expression data has also been used to predict prognosis of AML patients, identifying an adverse high MAPK gene signature. Genome-wide epigenetic (DNA methylation) profiling has added to AML prognostication. We analyzed patient prognosis and in vitro sensitivity for blasts by pathway-targeting agents, in relation to expression clusters defined by the results of GSEA profiling. Blast cell sensitivity was assayed using the agents: (Tyrosine kinase inhibitors for: Flt3: Sorafenib (Onyx/Bayer) and Syk/Flt3: R406 (AstraZeneca); Bortezomib (Millenium), a proteasome- and NFkB- inhibitor, inducer of endoplasmic reticulum (ER) stress; or the pan-histone deacetylase (HDAC) inhibitor, SBHA, Vorinostat analogue). A group of 70 AML cases was studied. GSEA's (Taqman/RQ-PCR, ABI) were performed on two different 31-gene platforms interrogating the interaction of tyrosine kinase survival pathways (eg. Flt3) with downstream epigenetic targets: tumor suppressor genes DAPK1, p16INK4a/CDKN2A, and RUNX3. Expression levels of these are responsive to input from c-jun/AP-1, non-canonical NFkB isoforms/HDAC's, polycomb genes, and ets/ERG, which were monitored. Analysis of overall patient survival (OS) by Kaplan-Meier plots revealed conformity with established outcomes for conventional cytogenetic categories. Also, poor-risk categories defined by normal karyotype Flt3ITD mutation, as well as high hoxA9 and meis1 expressions were recognized. Classification categories involving NKFlt3ITD/high hoxA9/meis1 or complex cytogenetics/high MAPK were most strictly separated by Kaplan-Meier curves, and by representation on the GSEA heatmaps, vs. CBF/PML-RAR translocations. Specific association, between repression of the tumor suppressor DAPK1 (normalized to c-jun, a transcriptional activator) with high expressions of hoxA9 and DAPK1-repressive, non-canonical NFkB/relB, was apparent in most NKFlt3ITD and tMLL cases. Also, a known functional interaction implicating high Id1 expression with its repression of p16INK4a(CDKN2A) was linked by their expression levels on GSEA. The DAPK1/CDKN2A clusters demonstrated significant overlap, often with additional RUNX3 repression. The DAPK1-repressed(R) clusters demonstrated independent prognostic importance. There was median OS for DAPK1-R cluster #1(lower MAPK signature) of 17 months vs. for DAPK1-R cluster #2 of 6 months. This latter cluster was described by higher MAPK signature evidenced by heightened transcript levels of BRCA1 [Bullinger et al. Blood, 2007], FoxM1, bcl-2, IL-1b. The dominant cytogenetic/molecularly-defined phenotypes represented in these DAPK1-R clusters were NKFlt3ITD+ve and tMLL. A very-high MAPK/complex cluster, evidenced median OS 4.5 months vs. good prognosis (low MAPK/DAPK1, and low hoxA9/meis1) group: median OS> 3 years. Interestingly, in vitro activity for the dual inhibitor R406 on blasts was greatest in the category with strongest repression of both p16INK4a/CDKN2A and DAPK1, and with lowest expression of syk transcripts (10-fold compared with high patient values), with a median IC50 of between 10 nM (tMLL)-100nM (Flt3ITD). By contrast, Sorafenib demonstrated its greatest activity in a high MAPK phenotype, including but not restricted to Flt3ITD+ve status. Bortezomib demonstrated median IC50 40 nM. However, high expression levels of FoxM1, putative Bortezomib target, were negatively-associated with its activity. SBHA, the HDAC inhibitor, demonstrated lower activity on a molar basis, but had important synergy with tyrosine kinase inhibitors, a property that was optimal in the context of Id1 hyperexpression. Bortezomib was strongly synergistic with Flt3/syk inhibitors, particularly on FltITD+ve blasts. Indeed, both Bortezomib and the HDAC inhibitor demonstrated by correlation analysis (coefficients=63.3 and 13.4, respectively) optimal activities with Id1 hyperexpression. In conclusion, a pathway-focused genetic and epigenetic prognostic classification that also reports targeting agent sensitivity was established and further validated in a phase I (Sorafenib/Vorinostat) trial in AML (H Sayar, these abstracts). Disclosures: Sayar: Onyx/Bayer: Research Funding.

Therapeutic Immune Monitoring of Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors: Focus on CD4+ CD25+ t Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4036-4036
Author(s):  
Ziyuan Lu ◽  
Na Xu ◽  
Xuan Zhou ◽  
Guanlun Gao ◽  
Lin Li ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Similar Proportion

Abstract Background and Objectives: In clinical, conventional Tyrosine Kinase Inhibitors (TKIs) including imatinib, dasatinib, and nilotinib are remarkably effective forms of therapy for certain types of solid cancers as well as Ph+ leukemias. In addition to the BCR-ABL target oncoprotein, they also inhibit certain off-target kinases (Eph, c-KIT, TEC, SRC). Some TKIs affect immune reconstitution as well as the proliferation, function, and activation of T cells. Certain TKIs have been known to have an especially strong effect on CD4+CD25+ T cells, also known as regulatory T Cells (Tregs). There is currently a gap in the clinical data available about on this area of study. Patients and methods: In this study, we collected 108 Peripheral Blood (PB) samples from patients in the Chronic Phase (CP) of Chronic Myeloid Leukemia (CML) at the time of diagnosis (n=31) and also the TKIs treatment. Groups consisted of individuals treated with TKIs like imatinib (n=12), dasatinib (n=11) and nilotinib (n=8), as well as healthy controls (n=15). We evaluated the quantity and function of Tregs from patients in the CML-CP at the time of diagnosis and during treatment with TKIs. Results: It was found that at diagnosis, patients with CML had a similar proportion and absolute number of lymphocytes compared to healthy donors. After TKIs treatment, proportions and absolute numbers of total T cellsACD4+ T cells and Tregs decreased at different degree. Moreover, thedecrease would be more and more significant as time goes on.Our results indicated that although these three TKIs show similar inhibitory effects in the proportion and number of Tregs in vivo, they have differential effects on the functions of Tregs in vitro. The proliferation, suppression, and expression of suppressive cytokines (IL-4,IL-10 and TGF-β) as well as suppression-associated molecules (FoxP3, GITR, and CTLA-4) of Tregs decreased in groups treated with imatinib and dasatinib. The decrease was not significant in the nilotinib-treated group. Conclusions: The results showed that imatinib and dasatinib have stronger inhibitory roles than nilotinib when it comes to regulating the number and functions of Tregs. These findings can be used to argue in favor of calls for personalized treatment and follow-up of CML patients during TKIs treatment, particularly for those patients who received combination therapy with allo-transplantation and post-transplant TKIs. Disclosures No relevant conflicts of interest to declare.

Pharmacological interactions of TKIs with the P-gp drug transport protein.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2536-2536 ◽  
Author(s):  
Sandra Roche ◽  
Kasper Pedersen ◽  
Grainne Dunne ◽  
Denis Collins ◽  
Aoife Devery ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Drug Transport ◽  
Kinase Inhibitors ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Clear Understanding ◽  
Pharmacological Interactions

2536 Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug transport proteins. P-gp is a transporter with two important roles in cancer drug therapy. If overexpressed in tumour cells it can cause drug resistance. However, P-gp, expressed in tissues as part of normal drug clearance mechanisms, is also involved in termination of drug action. Hence, TKI-mediated interactions with P-gp have significant therapeutic consequences. Methods: P-gp over-expressing cancer cell lines were used to determine the inhibitor or substrate status of tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib). Cell proliferation assays in combination with a potent P-gp inhibitor, or P-gp substrate were also employed. Findings were augmented using LC-MS-based quantitation of cellular levels of target drugs. Results: We summarise our findings of four distinct interactions with P-gp among various TKIs. Some agents have little interaction at conventional doses; others can act as P-gp inhibitors without being substrates; substrates without being inhibitors or substrates which also prevent the actions of the transporter.Eachof the investigated TKIs has a distinct relationship with P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is a substrate but not an inhibitor, while pazopanib has little interaction with P-gp. Other agents also have an effect on or are affected by P-gp to varying amounts with some of these interactions likely to be suprapharmacological. Conclusions: P-gp protein has important roles both in resistance and drug toxicology, hence, a clear understanding of the interaction of emerging drugs with this transporter is vital. Agents which are inhibitors of P-gp may have applications in drug resistance circumvention but may also greatly exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics; conversely the activity of P-gp substrate TKIs may be reduced by tumour overexpression of the transporter. Hence in vitro screening of TKI-transporter interactions may identify putative TKI resistance mechanisms, help guide the development of combination schedule trials and/or reducing unwanted treatment side effects.

FMS-Like Tyrosine Kinase 3–Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro

2009 ◽  
Vol 69 (7) ◽  
pp. 3032-3041 ◽  
Author(s):  
Nikolas von Bubnoff ◽  
Richard A. Engh ◽  
Espen Åberg ◽  
Jana Sänger ◽  
Christian Peschel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tandem Duplication ◽  
Kinase Inhibitors ◽  
Resistance Mutations ◽  
Internal Tandem Duplication
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