The Use of Asciminib to Inactivate BCR-ABL1 Through A Myristoyl Site Locking the BCR-ABL1 Protein into An Inactive Conformation in Patients with Resistant Chronic Myeloid Leukemia
Introduction: Chronic myeloid leukemia (CML) is a neoplasm that affects myeloid lineage blood cells1. In the US, CML affects 1-2 out of every 100,000 adults and accounts for approximately 15% of newly diagnosed adult leukemia cases2. CML is characterized by a non-heritable mutation that leads to a genetic translocation leading to the fusion of the BCR and ABL genes called the Philadelphia chromosome. The Philadelphia chromosome creates the BCR-ABL1 protein which is a constitutively active tyrosine kinase that promotes uncontrolled replication through downstream signaling pathways leading to unregulated proliferation of blood cells of the myeloid lineage2. Tyrosine kinase inhibitors (TKIs) have been developed to treat CML by eradicating malignant clones that contain the Philadelphia chromosome. However, despite the advancements with first, second, and third generation TKIs, approximately 30-40% of patients do not have an optimal response or lose response to TKI therapy. For those who are resistant to first generation, second generation, and currently approved third generation TKIs, the prognosis is poor with limited treatment options available1. Asciminib is a novel TKI that is an allosteric inhibitor that binds to a myristoyl site of the BCR-ABL1 protein, inactivating it. As it does not bind at the ATP site it is a possible treatment against both native and mutated BCR-ABL1 that could open new treatment methods for those with TKI resistant CML3. Methods: In one study, ABL001 (asciminib) was administered to mice bearing KCL-22 xenografts and KCL-22 tumors. ABL001 and nilotinib were administered together as well as in sequence as consecutive monotherapies4. In another study, cell lines derived from CML patients with various resistance mutations including compound mutations were studied with asciminib and ponatinib administered as monotherapies and together5. Results: When administered together with traditional TKIs like nilotinib, imatinib, or dasatinib, asciminib showed an additive effect against BCR-ABL14. In addition, asciminib and ponatinib synergize to induce growth arrest and apoptosis in patient-derived CML cell lines and murine Ba/F3 cells harboring BCR-ABL1T315I or T315I-incluiding compound mutations and in multi-resistant CML cells in general5. Conclusion: Asciminib provides several new avenues in the treatment of TKI resistant CML. Due to its unique binding site, it acts with a different mechanism when compared to traditional TKIs. This allows for it to circumvent many of the mutant-driven acquired resistances of available TKIs either as a monotherapy or in conjunction with another TKI and has been shown to be effective against the T315I mutation and compound mutations4.
- Wolfe HR, Rein LA. The evolving landscape of frontline therapy in Chronic phase chronic myeloid leukemia (CML). Current Hematologic Malignancy Reports. 2021;16(5):448-454. doi:10.1007/s11899-021-00655-z
- Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. American Journal of Hematology. 2018;93(3):442-459. doi:10.1002/ajh.25011
- Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. New England Journal of Medicine. 2019;381(24):2315-2326. doi:10.1056/nejmoa1902328
- Wylie AA, Schaefer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543(7647):733-737. doi:10.1038/nature21702. Published 2017 Mar 30.
- Gleixner KV, Filik Y, Berger D, et al. Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1T315I-compound mutations. Am J Cancer Res. 2021;11(9):4470-4484. Published 2021 Sep 15.