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Updated: Mar 11, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Identification and characterization of activating ABL1 1b kinase mutations: impact on sensitivity to ATP-competitive
1Biomedical Sciences Program, University of California, San Francisco, CA, USA.
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.
Insights
Ten new ABL1 point mutations activate kinases and cause cell transformation, remaining sensitive to ATP-competitive tyrosine kinase inhibitors (TKIs). These findings support TKI use in ABL1 mutations and resistance testing for allosteric inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pathologically activated ABL1 fusion kinases are validated therapeutic targets.
- The significance of numerous ABL1 proto-oncogene point mutations remains unclear.
- ABL1 point mutations can arise alongside BCR-ABL1 fusions due to chromosomal breakpoint locations.
Purpose of the Study:
- To identify and characterize novel ABL1 1b point mutations.
- To determine the functional impact of these mutations on kinase activity and cellular transformation.
- To assess the sensitivity of mutated ABL1 kinases to different classes of inhibitors.
Main Methods:
- Identification and sequencing of ten novel ABL1 1b point mutations.
- Functional assays to assess kinase activation and cellular transformation.
- In vitro testing of mutant ABL1 sensitivity to ATP-competitive and allosteric inhibitors.
Main Results:
- Ten novel ABL1 1b point mutations were identified, including two from clinical samples, causing constitutive kinase activation and transformation.
- All identified mutants remained sensitive to ATP-competitive tyrosine kinase inhibitors (TKIs).
- Some mutations near the myristoyl-binding pocket relieved autoinhibition, while others conferred resistance to allosteric inhibition independently of proximity.
Conclusions:
- ABL1 point mutations can confer constitutive kinase activity and transformation, supporting the clinical investigation of ATP-competitive TKIs.
- The coexistence of BCR-ABL1 and ABL1 point mutations in clinical cases warrants further study.
- Sequencing BCR-ABL1 and ABL1 1b is recommended for patients with acquired resistance to allosteric ABL1 inhibitors.
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