Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency
| Autor: | Charles L. Sawyers, John Nicoll, Neil P. Shah, Timothy P. Hughes, Susan Branford, Brian J. Skaggs, Ronald Paquette |
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| Rok vydání: | 2007 |
| Předmět: |
Genotype
Amino Acid Motifs Dasatinib Fusion Proteins bcr-abl Aurora inhibitor Biology medicine.disease_cause Sensitivity and Specificity Piperazines Cell Line Mice Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Humans Proto-Oncogene Proteins c-abl Protein Kinase Inhibitors neoplasms Alleles Mutation ABL Kinase Valine Imatinib General Medicine medicine.disease Thiazoles Pyrimidines Nilotinib Drug Resistance Neoplasm Benzamides Imatinib Mesylate Cancer research Drug Therapy Combination Research Article medicine.drug Chronic myelogenous leukemia |
| Zdroj: | Journal of Clinical Investigation. 117:2562-2569 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci30890 |
| Popis: | Molecularly targeted kinase inhibitor cancer therapies are currently administered sequentially rather than simultaneously. We addressed the potential long-term impact of this strategy in patients with chronic myelogenous leukemia (CML), which is driven by the fusion oncogene BCR-ABL. Analysis of BCR-ABL genotypes in CML patients who relapsed after sequential treatment with the ABL inhibitors imatinib and dasatinib revealed evolving resistant BCR-ABL kinase domain mutations in all cases. Twelve patients relapsed with the pan-resistant T315I mutation, whereas 6 patients developed novel BCR-ABL mutations predicted to retain sensitivity to imatinib based on in vitro studies. Three of these patients were retreated with imatinib (or the chemically related compound nilotinib) and responded; however, selection for compound mutants (2 or 3 BCR-ABL mutations in the same molecule) can substantially limit the potential effectiveness of retreating patients with inhibitors that have previously failed. Furthermore, drug-resistant mutations, when compounded, can increase oncogenic potency relative to the component mutants in transformation assays. The Aurora kinase inhibitor VX-680, currently under clinical evaluation based on its activity against the T315I mutation, is also effective against the other commonly detected dasatinib-resistant mutation in our analysis, V299L. Our findings demonstrate the potential hazards of sequential kinase inhibitor therapy and suggest a role for a combination of ABL kinase inhibitors, perhaps including VX-680, to prevent the outgrowth of cells harboring drug-resistant BCR-ABL mutations. |
| Databáze: | OpenAIRE |
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