Pharmacology of imatinib (STI571)

Buchdunger, Elisabeth; O'Reilley, Terence; Wood, Jeanette M.

doi:10.1016/s0959-8049(02)80600-1

Cited by 224 publications

(200 citation statements)

References 31 publications

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“…Based on these findings, we examined a subset of inhibitors of other NRTKs on Tf internalization to identify additional regulators of receptor-mediated endocytosis. Surprisingly, out of the various compounds tested, imatinib, a widely used and relatively specific inhibitor of c-Abl kinase (17)(18)(19)(20)(21), appeared most effective in reducing Tf endocytosis when tested in clone 9 rat hepatocytes. As shown in Fig.…”

Section: C-abl Kinase Activity Is Required For Efficientmentioning

confidence: 99%

“…Subsequently, we observed that treating different cultured hepatocyte cell lines with imatinib (17,18), a potent inhibitor of the c-Abl family of NRTKs, resulted in a near complete ablation of ligand uptake. More specific inhibition of c-Abl function through expression of inhibitory mutants and/or the use of c-Abl knock-out (KO) mouse embryonic fibroblasts (MEFs) both appear consistent with the concept that functional c-Abl is indispensable for TfTfR1 internalization.…”

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confidence: 99%

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The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

Cao

Schroeder

Chen

et al. 2016

Journal of Biological Chemistry

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Clathrin-mediated endocytosis of transferrin (Tf) and its cognate receptor (TfR1) is a central pathway supporting the uptake of trophic iron. It has generally been assumed that this is a constitutive process. However, we have reported that the non-receptor tyrosine kinase, Src, is activated by Tf to facilitate the internalization of the Tf-TfR1 ligand-receptor complex. As an extension of these findings, we have tested whether subsequent trafficking steps might be regulated by additional kinase-dependent cascades, and we observed a significant endocytic block by inhibiting c-Abl kinase by a variety of methods. Importantly, Tf internalization was reduced significantly in all of these cell models and could be restored by re-expression of WT c-Abl. Surprisingly, this attenuated Tf-TfR1 endocytosis was due to a substantial drop in both the surface and total cellular receptor levels. Additional studies with the LDL receptor showed a similar effect. Surprisingly, immunofluorescence microscopy of imatinib-treated cells revealed a marked colocalization of internalized TfR1 with late endosomes/lysosomes, whereas attenuating the lysosome function with several inhibitors reduced this receptor loss. Importantly, inhibition of c-Abl resulted in a striking redistribution of the chaperone Hsc70 from a diffuse cytosolic localization to an association with the TfR1 at the late endosome-lysosome. Pharmacological inhibition of Hsc70 ATPase activity in cultured cells by the drug VER155008 prevents this chaperone-receptor interaction, resulting in an accumulation of the TfR1 in the early endosome. Thus, inhibition of c-Abl minimizes receptor recycling pathways and results in chaperone-dependent trafficking of the TfR1 to the lysosome for degradation. These findings implicate a novel role for c-Abl and Hsc70 as an unexpected regulator of Hsc70-mediated transport of trophic receptor cargo between the early and late endosomal compartments.

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Section: C-abl Kinase Activity Is Required For Efficientmentioning

confidence: 99%

mentioning

confidence: 99%

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

Cao

Schroeder

Chen

et al. 2016

Journal of Biological Chemistry

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“…1 Although targeted cancer therapies may be more effective than other anticancer treatments and less harmful to normal cells, 2 Imatinib has been found to be associated with widely-occurring side effects, such as oedema, skin rash and ocular side effects, among which ocular side effects are generally under-reported and not well studied.…”

Section: Introductionmentioning

confidence: 99%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

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Imatinib-induced ophthalmological side-effects, including conjunctiva hemorrhage and periorbital oedema, although very common and still remain relatively little understood. The present study investigated the effects of genetic polymorphisms of drug targets and membrane transporters on these side effects. We found that the minor allele of EGFR rs10258429 and SLC22A1 rs683369 were significant risk determinants of conjunctival hemorrhage with OR of 7.061 (95%CI = 1.791-27.837, P = 0.005 for EGFR rs10258429 CT +TT vs CC), and 4.809 (95%CI = 1.267-18.431, P = 0.021 for SLC22A1 rs683369 GG+CG vs CC). The minor allele of SLC22A5 rs274558 and ABCB1 rs2235040 were protective factors to periorbital oedema with OR of 0.313 (95%CI = 0.149-0.656, P = 0.002 for SLC22A5 rs274558 AA+AG vs GG), and 0.253 (95%CI = 0.079-0.805, P = 0.020 for ABCB1 rs2235040 CT vs CC). These results indicated that variants in EGFR, SLC22A1, SLC22A5 and ABCB1 influenced the incidence of Imatinib-induced ophthalmological toxicities, and polymorphism analyses in associated genes might be beneficial to optimize Imatinib treatment.

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“…For some of these tumours, there is in vitro evidence of inhibition by imatinib (Buchdunger et al, 2002;Heinrich et al, 2002a). In contrast to CML, the inhibition of a single signalling pathway will not usually be sufficient to overcome the proliferative advantage of the tumour.…”

Section: Other Solid Tumoursmentioning

confidence: 99%

“…Imatinib inhibits other tyrosine kinases broadening the potential therapeutic utility to a range of neoplastic disorders (Buchdunger et al, 2002). The proto-oncogene C-KIT encodes the KIT tyrosine kinase, which serves as a receptor for stem cell factor.…”

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confidence: 99%

Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

Ross

Hughes

2004

Br J Cancer

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Over the past few years, a number of anticancer drugs have been developed that specifically target kinases known to be oncogenic. The leading drug in this area is imatinib mesylate, which targets ABL, KIT and PDGFR. It has been remarkably effective in the treatment of chronic myeloid leukaemia, although resistance remains a significant problem. From the imatinib experience in this setting, we present some principles of kinase inhibition that may have more general applicability in targeted anticancer therapy. It is clear that the identification of appropriate targets (activated kinases) and monitoring levels of response (to recognise emerging resistance) are essential to optimise clinical management.

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Pharmacology of imatinib (STI571)

Cited by 224 publications

References 31 publications

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

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