What causes resistance to imatinib?
Both de novo and acquired resistance have been observed in imatinib-treated CML patients. The most commonly described mechanisms associated with resistance are point mutations in the BCR-ABL gene that prevent imatinib from inhibiting kinase activity and BCR-ABL gene amplification.
Which kinase does imatinib target?
BCR-ABL is a type of protein known as a tyrosine kinase. Drugs known as tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the standard treatment for CML. These include: Imatinib (Gleevec)
What pathway does imatinib target?
3.13. Imatinib is a potent dual inhibitor of both transforming growth factor-b and platelet-derived growth factor receptor (PDGF-R) pathways, which are responsible for fibrosis and inflammation in cGVHD [97].
How does imatinib target BCR-ABL?
[51,52,53] Imatinib can trap the deregulated BCR-ABL1 oncoprotein once it transits through its inactive conformation. The resulting inhibition of BCR-ABL1 autophosphorylation and substrate phosphorylation blocks proliferation and induce apoptosis of CML cells.
How do you test Gleevec resistance?
Laboratory testing for Gleevec resistance mutations: The cDNA is subjected to PCR amplification using primers that span the translocation site. The PCR product is then subjected to capillary DNA sequencing of the ABL kinase domain, including the P-loop, catalytic domain, and activation loop.
What is the pathophysiology of imatinib resistance in chronic myeloid leukemia?
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants shoul …
Why are most imatinib-resistant mutants shifted to the Abl kinase inhibitors?
Crystallographic studies predict that most imatinib-resistant mutants shoul … Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding.
What is the pathophysiology of resistance to kinase inhibitors?
Resistance to kinase inhibitors can broadly be categorized as either innate or primary resistance, or acquired resistance. Even when tumours harbour an oncogenic driver mutation associated with sensitization to a specific kinase inhibitor, not all tumour cells respond and others exhibit only transient duration of benefit.
What is the resistance rate to imatinib (ibuprofen)?
The annual resistance rate to imatinib is 3% to 4% in the first 5 years. Resistance can be primary (mostly caused by BCR-ABL1–independent mechanisms—that is, with persistent inhibition of the BCR-ABL1 kinase) or secondary (after an initial response, most often due to BCR-ABL1–dependent mechanisms—that is, with reactivation of the BCR-ABL1 kinase).