What is the mechanism of action of Imatinib (Gleevec)?

From the Guidelines

Imatinib is a tyrosine kinase inhibitor that works by blocking specific enzymes called tyrosine kinases, particularly BCR-ABL, c-KIT, and PDGFR, with its primary mechanism involving competitive binding at the ATP-binding site of these kinases, preventing them from phosphorylating their substrate proteins and halting downstream signaling pathways essential for cancer cell growth and survival 1. The mechanism of action of imatinib is based on its ability to selectively inhibit the activity of certain tyrosine kinases, which are enzymes responsible for the activation of many proteins by signal transduction cascades. In the context of chronic myeloid leukemia (CML), imatinib specifically targets the BCR-ABL fusion protein, which results from the Philadelphia chromosome translocation and drives uncontrolled cell proliferation 1. By inhibiting this abnormal protein, imatinib effectively stops the growth of leukemic cells while largely sparing normal cells.

Key Points about Imatinib's Mechanism of Action

• Imatinib targets the BCR-ABL fusion protein in CML, preventing uncontrolled cell proliferation 1.
• It also targets mutated c-KIT or PDGFR-alpha receptors in gastrointestinal stromal tumors (GISTs), stopping continuous signaling for cell growth 1.
• The standard dosing for CML is typically 400-600 mg daily, while for GIST it's usually 400 mg daily, with dose adjustments based on response and tolerability.
• Imatinib should be taken with food and a large glass of water to minimize gastrointestinal side effects.
• The drug's selectivity for specific molecular targets explains its efficacy and relatively manageable side effect profile compared to traditional chemotherapy.

Clinical Evidence Supporting Imatinib's Mechanism of Action

• Studies have shown that imatinib induces durable responses in a large proportion of patients with CML, with estimated cumulative rates of complete cytogenetic response (CCyR) among patients receiving imatinib being 69% at 12 months and 87% at 60 months 1.
• In GISTs, imatinib has been shown to be effective in treating clinically advanced, metastatic, or surgically unresectable tumors, with a standard dose of 400 mg per day established from randomized phase III trials 1.

From the FDA Drug Label

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events

The mechanism of action of imatinib is through inhibition of protein-tyrosine kinases, specifically:

• BCR-ABL tyrosine kinase: created by the Philadelphia chromosome abnormality in CML
• Receptor tyrosine kinases: for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit This inhibition leads to apoptosis and inhibition of proliferation in affected cells 2

From the Research

Mechanism of Action of Imatinib

• Imatinib is a tyrosine kinase inhibitor that targets constitutively activated tyrosine kinases, such as BCR-ABL, c-KIT, and PDGFR 3, 4, 5.
• It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates 4.
• Imatinib has substantial activity in chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST) by inhibiting the BCR-ABL and c-KIT tyrosine kinases, respectively 3, 4.
• The drug has also shown efficacy in Philadelphia chromosome-positive acute lymphoblastic leukaemia and other cancers that over-express KIT or PDGFR 4, 6.

Resistance to Imatinib

• Resistance to imatinib can occur through several mechanisms, including mutations in the BCR-ABL kinase domain and amplification of the BCR-ABL gene 7, 6.
• Mutations in the kinase domain of BCR-ABL have been detected in approximately 51.6% of patients with secondary resistance to imatinib 7.
• Other mechanisms of resistance, such as clonal evolution and additional cytogenetic aberrations, have also been identified 7, 6.

Clinical Efficacy and Safety

• Imatinib has been shown to induce high rates of cytogenetic and molecular responses in CML and GIST patients, with a relatively low incidence of severe toxicities 3.
• Common adverse effects of imatinib include musculoskeletal and joint pain, muscle cramps, oedema, and gastrointestinal symptoms, which are generally grade I or II toxicities and occur during the early phase of treatment 3.