Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study

Ray, Arghya; Cowan‐Jacob, Sandra W.; Manley, Paul W.; Mestan, Jürgen; Griffin, James D.

doi:10.1182/blood-2006-01-015347

Cited by 130 publications

(98 citation statements)

References 30 publications

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“…Nilotinib is active against most imatinib-resistant mutants except T315I in both cell culture and murine models. 15,55,56 In a dose-ranging (50 mg once daily to 600 mg twice daily) phase 1 study in 119 patients with imatinib-resistant CML, nilotinib demonstrated activity in all phases of CML. 57 Eleven of 12 patients who had CML-CP (92%) had a CHR.…”

Section: Nilotinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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Identification of BCR‐ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR‐ABL inhibitor, is the standard of care for the first‐line treatment of patients with chronic‐phase CML because of its high long‐term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard‐dose imatinib (400 mg daily), imatinib dose escalation (600‐800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR‐ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second‐generation tyrosine kinase inhibitors dasatinib and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib‐resistant or imatinib‐intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.

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Section: Nilotinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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“…in combination with nilotinib or imatinib completely suppresses outgrowth of resistant clones by random mutagenesis screen To assess whether combinations of ABL kinase inhibitors offer an advantage over AUY922 alone, we carried out a random mutagenesis screens with combinations of AUY922 and imatinib or nilotinib (Ray et al, 2007). This approach uses a DNA repair-deficient Escherichia coli strain to produce random mutagenesis of a BCR-ABL retroviral plasmid, infection of BaF3 cells and selection for BaF3 clones conferring varying degree of drug resistance (Ray et al, 2007).…”

Section: Auy922mentioning

confidence: 99%

“…This approach uses a DNA repair-deficient Escherichia coli strain to produce random mutagenesis of a BCR-ABL retroviral plasmid, infection of BaF3 cells and selection for BaF3 clones conferring varying degree of drug resistance (Ray et al, 2007). Profiling of AUY922 as a single agent revealed a concentration-dependent reduction of colonies (Figure 1).…”

Section: Auy922mentioning

confidence: 99%

“…M351T is a sensitive mutation to nilotinib, on the other hand, E255K is an insensitive mutation to The approach uses a DNA repair-deficient Escherichia coli strain to produce random mutagenesis of a BCR-ABL retroviral plasmid, infection of BaF3 cells, and selection for BaF3 clones conferring varying degree of drug resistance using methods previously described (Azam et al, 2003). BaF3 cells expressing the random mutagenesis of BCR-ABL were kindly provided by Dr James D Griffin (Dana-Farber Cancer Institute) (Ray et al, 2007). BaF3 cells expressing the random mutagenesis of a BCR-ABL were cultured with graded concentrations of AUY922 alone and in combination with imatinib or nilotinib.…”

Section: Auy922mentioning

confidence: 99%

“…BaF3 cells expressing the random mutagenesis of BCR-ABL were kindly provided by Dr James D Griffin (Dana-Farber Cancer Institute, Boston, MA, USA) (Ray et al, 2007). BaF3 cells expressing WT BCR-ABL and mutant forms of BCR-ABL (M244V, G250E, Q252H, Y253F, T315A, T315I, F317L, F317V, M351T and H396P) were described previously (Deguchi et al, 2008).…”

Section: Cells and Cell Culturementioning

confidence: 99%

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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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Setting the Paradigm of Targeted Drugs for the Treatment of Cancer: Imatinib and Nilotinib, Therapies for Chronic Myelogenous Leukemia

Manley

Zimmermann

2012

Case Studies in Modern Drug Discovery and Development

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Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study

Cited by 130 publications

References 30 publications

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

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

Setting the Paradigm of Targeted Drugs for the Treatment of Cancer: Imatinib and Nilotinib, Therapies for Chronic Myelogenous Leukemia

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