A novel hyperactive <i>BCR::ABL1</i> <sup> <i>e6a3</i> </sup> variant confers resistance to combined asciminib plus ponatinib therapy
and cellular proliferation. These data show that treatment with asciminib and ponatinib can select for mutations with notably elevated enzymatic activity, effectively targeted by an axitinib-based triple combination. These data highlight the remarkable mutability of the BCR::ABL1 kinase, including through novel isoforms and provides a strong rationale for the clinical assessment of a triple inhibitor combination as a strategy to overcome resistance to dual ponatinib and asciminib therapy.
Authors
- Andrew Mark Brunner (ORCID: https://orcid.org/0000-0002-2169-4115)
- Areeba Khan (ORCID: https://orcid.org/0000-0001-7197-7984)
- Sekhu Ansari (ORCID: https://orcid.org/0000-0002-3968-5508)
- Mohammad Azam (ORCID: https://orcid.org/0000-0002-4274-2796)
- Zachary Kincaid (ORCID: https://orcid.org/0000-0002-7294-9165)
- Meenu Kesarwani (ORCID: https://orcid.org/0000-0003-3925-3809)
- Nicolas Nassar
- George Q. Daley (ORCID: https://orcid.org/0000-0002-6346-5919)
- Gabriel K. Griffin (ORCID: https://orcid.org/0009-0006-0185-1239)
- Noor Amir
- Joshua Schwieterman
- Mohammad Azhar
- Scott Ryall
- Tahira Yousuf
- Valentina Nardi (ORCID: https://orcid.org/0000-0002-0486-416X)
- Maria Reyes Capilla Guerra (ORCID: https://orcid.org/0009-0005-1199-4295)
Institutions
- Brigham and Women's Hospital (US)
- Cincinnati Children's Hospital Medical Center (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Center for Cancer and Blood Disorders (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- University of Cincinnati (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-04-24
- DOI
- https://doi.org/10.64898/2026.04.14.26349982
- Primary Topic
- Chronic Myeloid Leukemia Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health