Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

Bantscheff, Marcus; Eberhard, Dirk; Abraham, Yann; Bastuck, Sonja; Böesche, Markus; Hobson, Scott; Mathieson, Toby; Perrin, Jessica; Raida, Manfred; Rau, Christina; Reader, Valérie; Sweetman, Gavain; Bauer, Andreas; Bouwmeester, Tewis; Hopf, Carsten; Kruse, Ulrich; Neubauer, Gitte; Ramsden, Nigel G.; Rick, Jens M.; Küster, Bernhard; Drewes, Gerard

doi:10.1038/nbt1328

Cited by 976 publications

(1,117 citation statements)

References 44 publications

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“…Interestingly, dasatinib sensitively did not appear to correlate with the levels of Src activation in each cell line. Consistent with these findings, Src kinase failed to emerge as a marker predicting dasatinib sensitivity in breast cancer cell lines (41,42), underscoring the potential broad target specificity of this tyrosine kinase inhibitor (43,45). Although promising candidates have been identified, the direct mediators of dasatinib action in breast tumor cells remain to be confirmed.…”

Section: Discussionmentioning

confidence: 72%

“…We investigated the efficacy of the tyrosine kinase inhibitor dasatinib, currently in clinical use for the treatment of patients with refractory leukemias, as a single-agent in our preclinical assays. Although originally designed as a Src kinase family inhibitor, dasatinib appears to have broad tyrosine kinase specificity (43,45) and effectively inhibits breast tumor cell lines with the most aggressive phenotypes (41,42). Likewise, dasatinib suppressed each tumor cell line tested here including HER2Δ16-expressing trastuzumab-refractory tumor cell lines.…”

Section: Discussionmentioning

confidence: 98%

“…Dasatinib is currently in clinical trials for the treatment of solid tumors and has recently been shown to inhibit the growth and proliferation of multiple breast tumor cell lines (41,42). Although originally designed as a Src kinase family inhibitor, dasatinib displays broader than anticipated tyrosine kinase inhibitor activity including direct inhibition of receptor tyrosine kinases (42)(43)(44)(45).…”

Section: Her2δ16-expressing Cell Lines Are Sensitive To a Single-agenmentioning

confidence: 99%

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An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

Mitra

Brumlik

Okamgba

et al. 2009

Molecular Cancer Therapeutics

174

205

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The HER2-targeted therapy trastuzumab is widely used for the treatment of patients with metastatic breast tumors overexpressing HER2. However, an objective response is observed in only 12% to 24% of patients treated with trastuzumab as a single agent and initial responders regress in <6 months (1-3). The reason for the clinical failure of trastuzumab in this setting remains unclear. Here we show that local lymph node-positive disease progression in 89% of breast cancer patients with HER2-positive tumors involves the HER2 oncogenic variant HER2Δ16. We further show that ectopic expression of HER2Δ16, but not wild-type HER2, promotes receptor dimerization, cell invasion, and trastuzumab resistance of NIH3T3 and MCF-7 tumor cell lines. The potentiated metastatic and oncogenic properties of HER2Δ16 were mediated through direct coupling of HER2Δ16 to Src kinase. Cotargeting of HER2Δ16 and Src kinase with the singleagent tyrosine kinase inhibitor dasatinib resulted in Src inactivation, destabilization of HER2Δ16, and suppressed tumorigenicity. Activated Src kinase was also observed in 44% of HER2Δ16-expressing breast carcinomas underscoring the potential clinical implications of coupled HER2Δ16 and Src signaling. Our results suggest that HER2Δ16 expression is an important genetic event driving trastuzumab-refractory breast cancer. We propose that successful targeted therapeutics for intervention of aggressive HER2-positive breast cancers will require a strategy to suppress HER2Δ16 oncogenic signaling. One possibility involves a therapeutic strategy employing single-agent tyrosine kinase inhibitors to disengage the functionally coupled oncogenic HER2Δ16 and Src tyrosine kinase pathways.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 98%

Section: Her2δ16-expressing Cell Lines Are Sensitive To a Single-agenmentioning

confidence: 99%

See 1 more Smart Citation

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

Mitra

Brumlik

Okamgba

et al. 2009

Molecular Cancer Therapeutics

174

205

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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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“…Similar to the ICAT method, multiple peptide measurements can then be combined to result in relative abundance measurements at the protein level. The iTRAQ method has recently been used to monitor small molecule binding to proteins and map drug-induced changes in protein phosphorylation states in human cells, illustrating this method's potential use in drug discovery experiments [24]. However, although iTRAQ labeling allows for incorporation of labels into all peptides in a mixture (in contrast to ICAT), this inclusive feature inherently requires that the labeling be done after protease digestion, thereby limiting their use as internal standards because experimental variations at prior sample preparation steps are not accounted for.…”

Section: Stable Isotope Labeling Strategiesmentioning

confidence: 99%

Quantitative strategies to fuel the merger of discovery and hypothesis-driven shotgun proteomics

Kline¹,

Finney²,

Wu³

2009

Briefings in Functional Genomics and Proteomics

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The ultimate goal of most shotgun proteomic pipelines is the discovery of novel biomarkers to direct the development of quantitative diagnostics for the detection and treatment of disease. Differential comparisons of biological samples identify candidate peptides that can serve as proxys of candidate proteins. While these discovery approaches are robust and fairly comprehensive, they have relatively low throughput. When merged with targeted mass spectrometry, this pipeline can fuel hypothesis-driven studies and the development of novel diagnostics and therapeutics.

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Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

Cited by 976 publications

References 44 publications

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

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

Quantitative strategies to fuel the merger of discovery and hypothesis-driven shotgun proteomics

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