Preferred Label : Inhibition of Cellular Proliferation by Gleevec Pathway;
NCIt related terms : Inhibition of Cellular Proliferation by Gleevec;
Alternative definition : BIOCARTA: The drug Gleevec (also known as imatinib mesylate or STI-571) was approved
by the FDA in 2001 for the treatment of CML, chronic myeloid leukemia. While traditional
cytotoxic cancer treatments such as chemotherapy or radiation therapy kill all dividing
cells, Gleevec acts on a molecular target by a mechanism that is more specific to
cancer cells. Traditional cytotoxic cancer agents have serious side effects such as
nausea, weight loss, hair loss and severe fatigue that result from their lack of specificity
in killing cells. Gleevec was designed as an inhibitor of a specific receptor associated
with CML, and so produces less severe side effects than other cancer agents. CML is
associated in most cases with a specific chromosomal defect, a translocation between
chromosomes 9 and 22 that creates the Philadelphia chromosome. This translocation
creates the abnormal bcr-abl protein, a fusion of the Abl gene with another gene called
Bcr. The kinase activity of Abl in the bcr-abl fusion is activated and unregulated,
driving the uncontrolled cell growth observed in CML. White blood cells containing
the bcr-abl mutation become able to proliferate in the absence of growth factors they
normally require. Gleevec inhibits Abl kinase activity, helping to reverse uncontrolled
cell growth. Gleevec also inhibits the PDGF tyrosine kinase and the c-kit tyrosine
kinase. There are a variety of cellular substrates of the bcr-abl kinase that may
be involved in cellular transformation. Some of the downstream factors in bcr-abl
signaling include PI3 kinase/AKT and STAT transcription factors. The activation of
bcr-abl also represses apoptosis through induction of anti-apoptosis factors such
as Bad, allowing transformed cells to divide. JAK2 kinase activity appears to be one
target of bcr-abl. Grb-2 phosphorylation by bcr-abl may play a role in down-regulation
of tyrosine kinase signaling. STAT5 may be involved in the failure of apoptosis in
bcr-abl cells. In addition to supporting the idea that cancer therapies targeting
specific molecular targets should be efficacious with fewer side effects, Gleevec
has also demonstrated that drugs inhibiting protein kinases can be developed successfully.
Tyrosine kinases are important in a range of cellular processes, including other cancers,
and will provide additional drug targets. Gleevec itself has already demonstrated
potential in other cancers such as gastrointestinal stromal tumor that do not respond
to existing treatments. Although Gleevec has produced very strong clinical responses
in patients with early stage CML, patients with late stage disease have had an initial
response followed by a relapse of drug resistant CML cells. Cancer cells in patients
with Gleevec resistant cancer either had amplification of the bcr-abl gene, or mutation
of a key amino acid involved in binding drug from threonine to isoleucine. (This definition
may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_gleevecpathway;
Origin ID : C39094;
UMLS CUI : C1512774;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
