GIST Support WikiOne comment about resistant GIST with an exon 11 KIT mutation:
Frequently (though not always) acquired resistance to BOTH Gleevec and Sutent occurs when the GIST gains an EXTRA mutation in an area called exon 17 of KIT. This is called a "secondary mutation" because it is in addition to the primary mutation in exon 11 of KIT.
Exon 17 is part of the KIT protein that makes close physical contact with the shapes of the Gleevec or Sutent molecule. If exon 17 becomes mutated, then it distorts the binding pocket of KIT so that it is no longer fits nicely with the shape of Gleevec or Sutent.
AMN107 is similar to the Gleevec molecule in many ways EXCEPT that the parts of the molecule that come into close contact with exon 17 of KIT have been modified in AMN107. These modifications allow AMN107 to fit better into the protein in a way that its binding to KIT may not be reduced by mutations in exon 17. So AMN107 is reported to bind to KIT proteins that carry a common mutation in exon 17 called D816V--this particular mutation interferes with the binding of Gleevec and Sutent.
If I had a Gleevec and Sutent resistant GIST, then I would start hunting around for treatments that may work against exon 17 KIT mutations--even if I did not know that I had an exon 17 KIT mutation--the odds suggest it would be a real possibility. This would be the number one topic that I would discuss with my GIST specialist when choosing a trial.
Some considerations include IPI504 which accelerates the destruction of KIT, and would work even better against KIT proteins that become even more abnormal with secondary mutations. Though this is a phase I trial(as of 09/07), there are some attractive aspects--the trial has been around for a while and so they have a good idea of the therapeutic dose. Data has been released at ASCO showing benefit of some kind in a majority of the pts who reached the higher dosages, and the side effects seem minimal.