| Abstract: |
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. |
| Keywords: |
controlled study; treatment response; gene mutation; human cell; mutation; aurora kinase inhibitor; cyclopropanecarboxylic acid [4 [4 (4 methyl 1 piperazinyl) 6 (5 methyl 2h pyrazol 3 ylamino) 2 pyrimidinylthio]phenyl]amide; clinical trial; disease course; dose response; drug efficacy; drug withdrawal; nonhuman; sensitivity and specificity; mutant protein; animal cell; animals; mice; allele; imatinib; drug inhibition; controlled clinical trial; phase 2 clinical trial; protein kinase inhibitor; cell line; genetic variability; genotype; alleles; in vitro study; drug resistance, neoplasm; dasatinib; chronic myeloid leukemia; pyrimidines; protein kinase inhibitors; oncogene; hybrid protein; drug therapy, combination; cancer relapse; bcr abl protein; drug blood level; phase 1 clinical trial; piperazines; nilotinib; drug substitution; thiazoles; drug sensitivity; fusion proteins, bcr-abl; valine; amino acid motifs; carcinogen; proto-oncogene proteins c-abl; leukemia, myeloid, philadelphia-positive
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