gleevec resistance

[joshua_msu]

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hello all. i am trying to do some research on the mechanisms of gleevec resistance in chronic myelogenous luekemia, but am coming up short. i have searched many articles on pub med and the like, but many of them that i find seem to be too detailed in their biochemistry for most med students to understand. i am not being lazy, but just need some help or steering in the right direction. does anyone know of any good sources on the internet for this problem, or does nayone have some good knowledge they would like to share on this subject. thanks.

 

[Gleevec]

I knew that one day a fledgling SDN movement would arise to attempt to displace me.

Seriously though, resistance to Gleevec is due to a change in the conformation of the ATP binding pocket of the BCR-ABL kinase. CML is caused by a reciprocal translocation event that results in a hyperactive fusion kinase that causes cellular proliferation. What Gleevec does is it binds to the ATP binding pocket of the kinase, preventing further signaling. Its basically a molecule that clogs up this pocket. Unfortunately, further mutations and conformational changes in the ATP binding pocket domain have caused Gleevec to bind ineffectively to the BCR-ABL kinase. Thus, the kinase can use ATP and cause hyperactive cellular proliferation.

A good expanation of this is found in Nature 422, 827 - 828 (24 April 2003) by SARA A. COURTNEIDGE.

Try searching for "gleevec resistance review" in pubmed or "STI-571 resistance review".

Hope that helps.

In the future do not try to overthrow me. Resistance is futile.

😉

 

[kaos]

Originally posted by Gleevec

In the future do not try to overthrow me. Resistance is futile.

I saw that coming.

 

[joshua_msu]

ok thanks guys, that helped with what i needed. now i am looking for any insights on how the resistance may be overcome or treated later on.

 

[carrigallen]

Originally posted by joshua_msu
ok thanks guys, that helped with what i needed. now i am looking for any insights on how the resistance may be overcome or treated later on.

It is already being overcome. There are whole hosts of laboratories working with big pharma to create classes of drugs which would work upon the mutated receptors. The idea is that resistance can be combated by structurally analyzing the mutated receptors and designing very similiar drugs for them, before resistance even starts. Here is how the idea works:


1. Patient diagonosed with eligible pathology (ie gi cancer, cml, other c-kit type cancer).

2. Tissue sample sent to lab, genetically analysed for disposition towards particular mutations. (based on compiled database)

3. Drug regimen prescribed based on genetic suscepltibility to resistance (ie gleevec + 'meevec' +'sheevec' )

4. Gleevec wipes out existing cancer cells, and secondarily mutated cancer cells are inhibited by 'meevec' or 'sheevec'.


For more information, contact Dr. Corless [email protected]