Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations
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BMS-354825 (dasatinib) and AMN107 (nilotinib) are potent alternate Abl inhibitors with activity against many imatinib mesylate-resistant BCR-ABL kinase domain (KD) mutants, except T315I. We used N-ethyl-N-nitrosourea (ENU)-exposed Ba/F3-p210(BCR-ABL) cells to compare incidence and types of KD mutants emerging in the presence of imatinib mesylate, dasatinib, and nilotinib, alone and in dual combinations. Although ENU is expected to induce mutations in multiple proteins, resistant clones were almost exclusively BCR-ABL KD mutant at relevant concentrations of nilotinib and dasatinib, consistent with a central role of KD mutations for resistance to these drugs. Twenty different mutations were identified with imatinib mesylate, 10 with nilotinib (including only 1 novel mutation, E292V) and 9 with dasatinib. At intermediate drug levels the spectrum narrowed to F317V and T315I for dasatinib and Y253H, E255V, and T315I for nilotinib. Thus, cross-resistance is limited to T315I, which is also the only mutant isolated at drug concentrations equivalent to maximal achievable plasma trough levels. With drug combinations maximal suppression of resistant clone outgrowth was achieved at lower concentrations compared with single agents, suggesting that such combinations may be equipotent to higher-dose single agents. However, sequencing uniformly revealed T315I, consistent with the need for a T315I inhibitor, to completely block resistance.
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ENU mutagenesis studies have been predictive of clinical drug resistance mutations in several prior studies.
“However, ENU mutagenesis studies have been predictive of clinical drug resistance mutations in several prior studies (14, 24).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [24]
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- Authors
- Bradeen, H. A., Eide, C. A., O'Hare, T., Johnson, K. J., Willis, S. G., Lee, F. Y., Druker, B. J., & Deininger, M. W.
- Affiliations
- Howard Hughes Medical Institute (US)
- From the Oregon Health & Science University Cancer Institute, Portland; the Howard Hughes Medical Institute, Portland, OR; and Bristol-Myers Squibb Oncology, Princeton, NJ.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-10-01
- Volume
- 108
- Issue
- 7
- Pages
- 2332-2338
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895563
- OpenAlex
- W2159863363
- Cited by
- 393
- References
- 35
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 13 · 2023: 8 · 2022: 5 · 2021: 12 · 2020: 9 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 14 · 2015: 21 · 2014: 18 · 2013: 17 · 2012: 25
- FWCI
- 26.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL082978, HL082978-01)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- imatinib mesylate, dasatinib, nilotinib, BCR-ABL, ABL kinase inhibitors, drug resistance, kinase domain mutations, T315I mutation, cross-resistance, combination therapy, mutagenesis screen, N-ethyl-N-nitrosourea, Ba/F3 cells, chronic myeloid leukemia
- MeSH terms
- Imatinib Mesylate, Dasatinib, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Drug Screening Assays, Antitumor, Ethylnitrosourea, Humans, Mutagens, Piperazines, Pyrimidines, Thiazoles, Fusion Proteins, bcr-abl, Point Mutation, Protein Structure, Tertiary, Inhibitory Concentration 50
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