scholarly journals Tyrosine Kinase Inhibitors as Reversal Agents for ABC Transporter Mediated Drug Resistance

Molecules ◽  
2014 ◽  
Vol 19 (9) ◽  
pp. 13848-13877 ◽  
Author(s):  
Nagaraju Anreddy ◽  
Pranav Gupta ◽  
Rishil Kathawala ◽  
Atish Patel ◽  
John Wurpel ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Abc Transporter ◽  
Kinase Inhibitors ◽  
Reversal Agents

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.

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.

Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents

2017 ◽  
Vol 142 ◽  
pp. 271-289 ◽  
Author(s):  
Giovanni Luca Beretta ◽  
Giuliana Cassinelli ◽  
Marzia Pennati ◽  
Valentina Zuco ◽  
Laura Gatti
Keyword(s):  
Multidrug Resistance ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Abc Transporter ◽  
Kinase Inhibitors ◽  
Dual Role

Microenvironmental Factors Determine the Sensitivity of Acute Myeloid Leukemia Cells to Tyrosine Kinase Inhibitors.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1630-1630
Author(s):  
Akira Shimada ◽  
Shelley Orwick ◽  
Hiroyuki Fujisaki ◽  
Dario Campana ◽  
Sharyn D. Baker
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Protective Effect ◽  
Tyrosine Kinase Inhibitors ◽  
Direct Contact ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Soluble Factors ◽  
Acute Myeloid

Abstract There is an increasing body of evidence indicating that the bone marrow microenvironment can generate drug resistance in acute leukemia. The mechanisms underlying this effect have not yet been elucidated; signals triggered by direct contact with extracellular matrix components and by mesenchymal cell (MSC)-secreted factors have been implicated. The protective effect of the microenvironment has been primarily observed for classical chemotherapeutic drugs. Recent reports, however, indicate that this can also occur with molecularly targeted therapies. Thus, it was shown that interleukin (IL)-7 desensitizes BCR-ABL+ leukemic cells to imatinib (Williams RT et al. Genes Dev 2007) and MSC-conditioned media protects BCR-ABL+ cells to imatinib and nilotinib (Weisberg E at al. Mol Cancer Ther, 2008). Several tyrosine kinase inhibitors are in clinical development for the treatment of acute myeloid leukemia (AML). The aim of this study was to determine whether bone marrow MSC affected the sensitivity of AML cells to 3 promising tyrosine kinase inhibitors (sorafenib, sunitinib, and midostaurin) and, if so, to begin to elucidate the underlying mechanisms. Using proliferation assays, we found that 3 AML cells lines (MV4-11, U937, and THP1) were significantly less sensitive to the tyrosine kinase inhibitors when cultured in the presence of bone marrow-derived MSC for 24h before exposure to drugs for 72h. In experiments with MV4-11, IC50 increased from 4.7 nM to 55 nM for sorafenib, from 10 nM to 110 nM for sunitinib, and from 28 nM to 135 nM for midostaurin; in experiments with U937, IC50 increases were 5.1 μM to 11 μM, 6.2 μM to > 10 μM, and 230 to > 1000 nM for each drug; and in experiments with THP1, they were 6.3 μM to 11 μM, 2.2 μM to > 10 μM, and 211 nM to 996 nM. Coculture with MSC also reduced sorafenib- and sunitinib-induced apoptosis by > 60%. Interestingly, drug resistance increased even further after coculturing the cell lines with MSC for 4 weeks or longer: sunitinib had virtually no effect on the proliferation of MV4-11 cells at concentrations of up to 100 nM, and on THP-1 cells at 10 μM. To determine whether the induction of drug resistance was dependent on the direct contact of AML cells with MSC, we tested sensitivity to sorafenib after separating MV4-11cells from MSC with transwell inserts. Under these conditions, the protective effect of MSC was lessened but not abrogated. These results indicated that direct contact with MSC was not an absolute requirement for induction of drug resistance and that MSC-secreted soluble factors might be, at least in part, involved. We therefore determined the soluble factors secreted by MSC using a multiplex assay and tested whether their secretion was augmented by contact with AML cells. MSC secreted IL-6 (230 pg/mL), IL-8 (1880 pg/mL), and VCAM-1 (30 pg/mL). When cocultured with MV4-11, U937 and THP-1 cells for 24h, IL-6 secretion increased 1.3 to 1.8-fold, IL-8 increased 1.5 to 2.6-fold, and VCAM-1 increased 2.2 to 5.6-fold; after 72 of coculture, dramatically elevated levels of IL-6 (2140–3869 pg/mL), IL-8 (4296–8068 pg/mL), and VCAM-1 (5109–6389 pg/mL) were observed. The effects of these and other MSC-derived factors on the sensitivity of AML cells lines and primary AML cells to tyrosine kinase inhibitors are being tested. These results indicate that the anti-AML effect of tyrosine kinase inhibitors is strongly inhibited by bone marrow MSC cells, and support the concept that the microenvironment is an important determinant of resistance to these agents in leukemia. We suggest that the development of agents that interfere with the interaction between AML cells and MSC, and with the molecular mechanisms underlying this protective effect of MSC is a crucial step to improve cure rates.

Sign in / Sign up

Export Citation Format

Share Document