Advances in the investigation of the molecular biology of cancer over several decades have made it possible to rationally design drugs to target oncogenic events with unprecedented specificity34. One such drug, Glivec® (imatinib), has rapidly become the standard of care for patients with advanced GIST6. Glivec is the first protein-tyrosine kinase inhibitor to reach the clinic and is thus the most established molecularly targeted agent of its class. It differs from radiation and chemotherapeutic agents in having a well-characterised mechanism of action and in exerting its effects on a particular abnormal protein found in nearly all patients with advanced GIST. In clinical trials, Glivec demonstrated efficacy in GIST superior to that achieved with previous systemic therapies, and it has been well tolerated by patients. The following section discusses Glivec in detail.
The success of Glivec in targeting the causative genetic abnormality that results in constitutive activation of the BCR-ABL tyrosine kinase in chronic myeloid leukaemia (CML) paved the way for the discovery of additional pathogenetic targets. The hallmark of GIST, the KIT protein-tyrosine kinase, is mutated in most patients with GIST (95%). About one third of the remaining GISTs are found to have abnormal PDGFRα16. These 2 proteins are responsible at the molecular level for GIST tumorigenesis. Glivec specifically targets most activating mutations in KIT and PDGFRα seen in patients with GIST6. Glivec targets the molecular causes of GIST and is an effective and generally well-tolerated oral therapy. By inhibiting the specific cause of the disease, Glivec brings to fruition the promise of molecularly targeted therapy in solid tumours as well as in haematological malignancy.
Glivec: The Paradigm of Molecularly Targeted Therapy
Glivec Indication
Glivec is indicated for the treatment of adult patients with KIT (CD117)-positive unresectable and/or metastatic malignant GIST35.
The recommended starting dose for adult patients in whom Glivec therapy is indicated is 400 mg/d for patients with unresectable and/or metastatic malignant GIST35.
Please refer to local prescribing information for specific indications.
Glivec Mechanism of Action
Glivec is an orally available member of the 2-phenylaminopyrimidine class of small molecules that were rationally designed to competitively bind to the ATP-binding pocket of specific tyrosine kinases36.
Glivec competitively inhibits ATP from binding to the nucleotide binding pocket of specific tyrosine kinase receptors, including KIT (see Figure 1) and PDGFR. Competitive inhibition prevents the transfer of phosphate groups from ATP to tyrosine residues on substrate proteins, referred to as phosphorylation. This selectivity for KIT and PDGFR, which are present in malignant GISTs, results in inhibition of cell proliferation and restoration of apoptosis37,38. KIT mutations are common in GIST and, together with PDGFRA mutations, predict efficacy of Glivec therapy.
Figure 1: Glivec binding to specific tyrosine kinase receptors37,38.
Glivec inhibits members of the class 3 family of receptor tyrosine kinases at micromolar concentrations, including KIT, the receptor for SCF, PDGFRα and PDGFRβ39. Additionally, Glivec inhibits ABL and BCR-ABL at concentrations in the micromolar range in vitro40. Glivec has also been shown to inhibit macrophage colony-stimulating factor receptor c-Fms39,41. ARG, another cytoplasmic protein-tyrosine kinase structurally related to ABL, is also inhibited by Glivec (Table 1)42.
Table 1. Glivec Selectively Inhibits Tyrosine Kinases in Addition to BCR-ABL and KIT |
Inhibited Kinases |
Kinases Not Inhibited |
BCR-ABL |
EGFR-RICD |
v-Scr |
v-Abl |
Her-2/neu |
c-Fgr |
c-Abl |
Insulin receptor |
Fit-1 |
Tel-Abl |
IGF-I-R |
Tek |
PDGFRα |
c-Lyn |
c-Met |
PDGFRβ |
Fit-3 |
PPK |
Tel-PDGFR |
Kdr |
|
KIT |
Jak-2 |
|
Arg |
TPK |
|
cFMS |
cScr |
|
|
GIST MOA animation
Find out about efficacy, dosing, and side effects in Prescribing Glivec.
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