title: Identification and characterization of activating ABL1 1b kinase mutations: impact on sensitivity to ATP-competitive and allosteric ABL1 inhibitors.
abstract: Although pathologically activated ABL1 fusion kinases represent well-validated therapeutic targets, tumor genomic sequencing has identified numerous point mutations in the ABL1 proto-oncogene of unclear significance. Here we describe ten novel ABL1 1b point mutations, including two from clinical isolates, that cause constitutive kinase activation and cellular transformation. All mutants retained sensitivity to ATP-competitive tyrosine kinase inhibitors (TKIs). Several substitutions cluster near the myristoyl-binding pocket, the target of ABL001, a novel clinically active allosteric kinase inhibitor that mimics the autoinhibitory myristoyl group, and likely activate the kinase by relieving physiologic autoinhibition. In addition, several mutations activate the kinase and confer resistance to allosteric inhibition despite a lack of proximity to this region. We demonstrate that BCR-ABL1 and ABL1 1b point mutations can co-exist in a proportion of clinical cases as a consequence of the chromosome 9 breakpoint location. Collectively, our findings support clinical investigation of ATP-competitive TKIs in malignancies harboring ABL1 point mutations, and sequencing of BCR-ABL1 and ABL1 1b in patients with acquired resistance to allosteric ABL1 inhibitors.
authors.affiliation: Biomedical Sciences Program, University of California, San Francisco, CA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: Biomedical Sciences Program, University of California, San Francisco, CA, USA.|Division of Hematology/Oncology, University of California, San Francisco School of Medicine, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: N P
authors.initials: NP
authors.lastname: Shah
mesh_terms: D000255:Adenosine Triphosphate; D000494:Allosteric Regulation; D001665:Binding Sites; D002460:Cell Line; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D019814:Myristic Acid / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D019814:Myristic Acid; D000255:Adenosine Triphosphate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl