Imatinib is a competitive tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably of which includes Philadelphia Chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML). Like all tyrosine-kinase inhibitors, Imatinib works by blocking a central tyrosine kinase enzyme, in this case, BCR-ABL from phosphorylating subsequent proteins and initiating the signaling cascade necessary for cancer development. Because the BCR-ABL tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, Imatinib is able to function as a targeted cancer therapy—only cancer cells are killed through the drug’s action. In this regard, Imatinib was one of the first cancer therapies to show the potential for such targeted action and of is often cited as a paradigm for research in cancer therapeutics
Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis.
Gastrointestinal Stromal Tumors
The FDA first granted approval for advanced GIST patients in 2002. On February 1st, 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence. The drug is also approved in unresectable KIT-positive GIST
The FDA has approved imatinib for use in adult patients with relapsed or refractory Ph-positive ALL, myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, aggressive systemic mastocytosis (ASM) without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans
The most common side effects include: feeling sick (nausea), diarrhoea, headaches, leg aches/cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite; weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), headache, and edema. Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium. If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty.
Mechanism Of Action
Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.
There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor). In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.
This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation. Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.
The Bcr-Abl pathway has many downstream pathways including the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth. It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.