Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets

Rix, Uwe; Hantschel, Oliver; Dürnberger, Gerhard; Rix, Lily; Planyavsky, Melanie; Fernbach, Nora V.; Kaupe, Ines; Bennett, Keiryn L.; Valent, Peter; Colinge, Jacques; Köcher, Thomas; Superti‐Furga, Giulio

doi:10.1182/blood-2007-07-102061

Cited by 604 publications

(620 citation statements)

References 42 publications

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Section: Other Severe Non-hematologic Events Observed During Nilotinibmentioning

confidence: 99%

“…Recent data suggest that nilotinib binds to a limited number of key kinasetargets including KIT and PDGFR both of which are also recognized by imatinib [19,20]. However, other kinase targets may preferentially be recognized by nilotinib [19,20]. One of the more interesting kinase-targets in terms of vascular cells and events is the discoidin domain receptor 1 (DDR1) [20,29].…”

Section: Other Severe Non-hematologic Events Observed During Nilotinibmentioning

confidence: 99%

“…First, nilotinib is a major blocker of KIT and PDGFR, two receptor kinases that have been implicated in the regulation of various vascular and perivascular cells [19,20]. Likewise, KIT is a major regulator of growth, survival, migration, and function of mast cells [34,35].…”

Section: Other Severe Non-hematologic Events Observed During Nilotinibmentioning

confidence: 99%

“…Similar to imatinib, nilotinib also inhibits the TK activity of PDGFR and KIT [18]. Although the primary mechanism of action of nilotinib in CML may relate to the inhibitory effects on BCR/ABL, additional effects of this drug on other targets [19,20] may also contribute to antileukemic effects, and possibly also to side effects of this drug.…”

Section: Introductionmentioning

confidence: 99%

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Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML

et al. 2011

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The second generation BCR/ABL kinase inhibitor nilotinib is increasingly used for the treatment of imatinib‐resistant chronic myeloid leukemia (CML). So far, nilotinib is considered a well‐tolerated drug with little if any side effects, although an increase in the fasting glucose level has been reported. We examined a series of 24 consecutive CML patients treated with nilotinib in our center for the development of non‐hematologic adverse events. Three of these 24 CML patients developed a rapidly progressive peripheral arterial occlusive disease (PAOD) during treatment with nilotinib. In all three cases, PAOD required repeated angioplasty and/or multiple surgeries within a few months. No PAOD was known before nilotinib‐therapy in these patients, although all three had received imatinib. In two patients, pre‐existing risk factors predisposing for PAOD were known, and one of them had developed diabetes mellitus during nilotinib. In the other 21 patients treated with nilotinib in our center, one less severe PAOD, one myocardial infarction, one spinal infarction, one subdural hematoma, and one sudden death of unknown etiology were recorded. In summary, treatment with nilotinib may be associated with an increased risk of vascular adverse events, including PAOD development. In a subgroup of patients, these events are severe or even life‐threatening. Although the exact mechanisms remain unknown, we recommend screening for pre‐existing PAOD and for vascular risk factors such as diabetes mellitus in all patients before starting nilotinib and in the follow up during nilotinib‐therapy. Am. J. Hematol. 2011. © 2011 Wiley‐Liss, Inc.

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Section: Other Severe Non-hematologic Events Observed During Nilotinibmentioning

confidence: 99%

Section: Other Severe Non-hematologic Events Observed During Nilotinibmentioning

confidence: 99%

Section: Other Severe Non-hematologic Events Observed During Nilotinibmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML

et al. 2011

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“…Besides the ABL kinases, the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 are target molecules for nilotinib (Bantscheff et al, 2007;Rix et al, 2007). T315I BaF3 cells were cultured with the indicated concentrations of nilotinib for 24 h, the cell lysates were Combined effects of AUY922 and nilotinib T Tauchi et al immunoprecipitated with anti-DDR1 antibody (Ab) and then immunoblotted with anti-phosphotyrosine mAb (PY20) or anti-DDR1 Ab (Figure 5a).…”

Section: Auy922 Induces Degradation Of Wt and Mutant Forms Of Bcr-ablmentioning

confidence: 99%

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

et al. 2011

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To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR-ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR-ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR-ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 lM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR-ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR-ABL-expressing cells.

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Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications

et al. 2017

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Metastatic dissemination of tumor cells is responsible for the fatal outcome of breast cancer. Therefore, understanding the mechanisms involved in dissemination is essential for the development of new therapeutic strategies to prevent metastasis. One mechanism involved in metastatic dissemination of breast cancer cells is dependent on control of the production of matrix metalloproteinases by the neuregulins (NRGs). The NRGs are polypeptide factors that act by binding to the ErbB/HER subfamily of receptor tyrosine kinases. NRG‐mediated activation of HER receptors causes an increase in the production of metalloprotease 13 (MMP13, also termed collagenase‐3), which facilitates metastatic dissemination of breast tumors. In this context, we aimed to explore whether the clinically approved tyrosine kinase inhibitor dasatinib was able to neutralize this mechanism of metastatic dissemination. Here, we show that dasatinib restricted NRG‐induced MMP13 upregulation, both in vitro and in vivo, and in vivo metastatic dissemination of breast cancer cells. Chemical proteomics studies showed that the main cellular targets of dasatinib were SRC family kinases (SFKs). Moreover, genetic studies showed that knockdown of SRC or YES strongly inhibited NRG‐induced MMP13 upregulation in vitro. Mechanistically, dasatinib treatment or knockdown of SRC also inhibited ERK1/2 kinases in vitro, which were required for NRG‐induced MMP13 upregulation. These results open the possibility of clinically exploring the antitumoral action of dasatinib in those tumors in which the NRG–MMP13 signaling axis may play a relevant role in the control of tumor cell dissemination.

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Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets

Cited by 604 publications

References 42 publications

Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML

Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

Regulation of the prometastatic neuregulin–MMP13 axis by SRC family kinases: therapeutic implications

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