This is the last article in a series discussing mutational status and resistant GIST. In this issue, we will discuss KIT exon 11 and exon 9 GIST. For an introduction and overview of this topic, see the first article which appeared in the September 2009 Clinical Trials Bulletin.
In the not too distant future, we may have newer KIT inhibitors that overcome most types of GIST resistance. But for the present, it is becoming increasingly clear that GIST can be divided into four main types based on mutational status; KIT exon 11, KIT exon 9, PDGFRA D842V and wild-type GIST. In addition, there is another group comprising the “rare” mutations (KIT exons 13 & 17, etc.). The different types have different initialresponses to Gleevec and resistance occurs via different mechanisms. GIST patients and doctors can use this knowledge to their advantage in choosing a clinical trial or, in some cases, to consider off-label treatment options.
KIT exon 11 and exon 9 mutations represent the two most common types of mutations (wild-type GIST is technically not a type of mutation but a lack of mutations) found in GIST patients. About 60 to 65 percent of GIST patients have a KIT exon 11 mutation and about 10 to15 percent have a KIT exon 9 mutation.
Gleevec/Sutent resistance in KIT exon 11 and exon 9 patients is different than resistance in wild-type or D842V mutations. The primary difference between exon 11/9 types and other types is that exon 11 resistance is driven primarily by secondary mutations. Exon 9 type tumors may not develop secondary mutations as often as exon 11 tumors, but in some cases multiple secondary mutations have been noted in exon 9 patients, especially upon resistance to Sutent.
Note: In this article, resistance refers primarily to resistance after both Gleevec and Sutent. It is already fairly well established that exon 9 tumors respond poorly to standard doses of Gleevec, respond fairly well to highdose (800 mg) Gleevec and respond well to Sutent.
Secondary mutations create a problem in GIST because they prevent Gleevec from binding to KIT and thus they cause resistance to Gleevec. Sutent effectively inhibits secondary exon 13 and exon 14 mutations, but it is not effective when the secondary mutation occurs in exon 17 or 18 (the activation loop). Compounding the problem, resistant patients frequently develop more than one secondary mutation. In one study of patients undergoing debulking surgery by Leigl and colleagues, 83 percent of patients with KIT mutations had secondary KIT mutations and in 2/3 of the patients there were two to five different secondary mutations.
While secondary mutations are a major problem with exon 11 and exon 9 patients, wild-type patients do not develop secondary mutations. At the present time, secondary mutations are probably not much of a problem with D842V patients either, because secondary mutations form, or become dominant, over time and patients with D842V mutations are resistant to drug treatment right from the start (primary resistance). Patients with the D842V mutation probably don’t have enough time on effective drug therapy for secondary mutations to become dominant. This may change in the future if patients have long-term responses to effective D842V inhibitors.
So, in contrast to wild-type GIST and D842V mutations, the first thing that a drug will need to do to be effective against secondary resistance in exon11 and exon 9 patients will be to target secondary mutations. There are several possible ways to do this and two of these are a little more developed. The two most developed approaches are:
• Inhibit KIT with a KIT tyrosine kinase inhibitor with very broad activity against exon 11/9 mutants with secondary mutations.
1. Sorafenib (Nexavar) is an example of an approved KIT inhibitor (approved for kidney and liver cancer) with better, but still not good enough, activity against secondary mutations.
2. The switch pocket kinase inhibitors being developed by Deciphera Pharmaceuticals are an example of very potent KIT inhibitors that also have wide-spectrum activity against secondary mutations.
• Destroy the KIT protein instead of merely blocking the signal. Hsp90 inhibitors use this method. Since the KIT protein is dependent on Hsp90, inhibiting Hsp90 results in destruction of the KIT protein, regardless of secondary mutations in KIT. HDAC inhibitors also use this method, but also have other effects.
1. STA-9090 is a very potent second generation Hsp90 inhibitor. A phase II trial for GIST is due to open very soon.
A third approach that is slightly less developed is to target critical pathways downstream of KIT. The leading candidate in downstream pathways appears to be PI3-K. There are a number of PI3-K inhibitors in phase I clinical trials.
Other approaches to overcome secondary mutations are to prevent the production of the KIT protein, for example to inhibit KIT transcription (bortezomib and flavopiridol), and to prevent activation of KIT by blocking receptor dimerization. These approaches seem to be less developed than the first two.
While secondary mutations form the major mechanism of resistance for exon 11 tumors and a smaller, but still significant percentage for exon 9 mutations, they are not the only mechanism that cause resistance in these tumors. The mechanisms affecting exon 9 tumors are not as clear as those affecting exon 11 or other types. KIT amplification (too much KIT protein) as well as activation of an alternate kinase has also been noted in resistant GIST. In particular, AXL kinase has been noted to be upregulated in some GISTs that have lost KIT expression and focal adhesion kinase (FAK) may also play a role in GIST tumor cell survival. Of note, MP470, a multi-tyrosine kinase inhibitor in phase I clinical trials, is reputed to be a wide-spectrum KIT inhibitor and also an AXL inhibitor.
For resistant exon 11 tumors, overcoming secondary mutations with a wide -spectrum KIT inhibitor or via HSP90 inhibition is the first priority. Though perhaps not as frequent, secondary mutations also appear to be a problem for resistant exon 9 tumors. Other mechanisms of resistance have been noted for these mutations including KIT protein overexpression and activation of alternate kinases. The relative infrequency of KIT overexpression and alternate kinase activation combined with a lack of clinical testing to identify these mechanisms makes targeting them difficult at this time, although very potent KIT inhibitors that also have a wide spectrum of activity (such as the Deciphera compounds in preclinical development) may naturally target protein overexpression as well as secondary mutations.