title: Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency.
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.
authors: Division of Hematology/Oncology, Department of Medicine, UCSF School of Medicine, San Francisco, California, USA.
authors: Neil P
authors: NP
authors: Shah
authors: Brian J
authors: BJ
authors: Skaggs
authors: Susan
authors: S
authors: Branford
authors: Timothy P
authors: TP
authors: Hughes
authors: John M
authors: JM
authors: Nicoll
authors: Ronald L
authors: RL
authors: Paquette
authors: Charles L
authors: CL
authors: Sawyers
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001549:Benzamides; D002460:Cell Line; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D013844:Thiazoles / Q000627:therapeutic use; D014633:Valine / Q000235:genetics / Q000378:metabolism; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D001549:Benzamides; D000069439:Dasatinib; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D016315:Proto-Oncogene Proteins c-abl; D011743:Pyrimidines; D013844:Thiazoles; D014633:Valine; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles
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