GIST mutation top cause Gleevec failure

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Editor’s note: This review was written by Jerry Call, Life Raft Group science coordinator, with input by Norman J. Scherzer, Life Raft Group executive director and David Josephy, Ph.D., Life Raft Group science advisor.

While Gleevec initially works very well for most GIST patients, cancer can eventually become resistant to the drug. Dr. Jonathan Fletcher of Dana-Farber Cancer Institute in Boston, and others presented some preliminary data about this problem at the 2003 convention of the American Society of Clinical Oncology. They noted four types of resistance in GIST:

1. Resistance due to acquisition of a secondary mutation (evolution of secondary KIT or PDGFRA mutants).
2. Resistance through overexpression (the tumor cells produce greater amounts of c-kit, the target kinase).
3. Activation of alternate mechanisms (kinase switching [e.g. KIT] to unknown kinase).
4. Functional resistance: Little is known about this type of resistance. It includes intrinsic (initial) resistance and may include undetermined factors.

Further research has found that acquisition of a secondary mutation appears to be the most common reason for resistance. As reported extensively in other articles, the primary genetic defects that drive GIST tumors are mutations in the c-Kit gene (in about 80 to 90 percent of cases) and the PDGFRA gene (about 5 percent of cases). Mutations can occur in different parts of the gene called “exons.” The c-Kit and PDGFRA genes contain information (a code or blueprint) that determines how the KIT receptor and the PDGFR receptor are assembled. These receptors are a type of protein.

Proteins have complex threedimensional shapes that allow them to carry out their normal function (such as signaling) in the cell. A mutation in the gene changes the shape of the protein, which changes its ability to function correctly. The mutations that occur in the c-Kit and PDGFRA genes typically result in the respective receptor being converted into a “constanton” state.

For the KIT or PDGFRA receptors to perform normal signal transduction functions, a chemical called ATP (adenosine triphosphate) must bind to a site in a section of the receptor called the kinase domain. The kinase domain has a three-dimensional shape and, like a key fitting into a lock, Gleevec fits into the ATP binding site in the kinase domain and blocks ATP. This prevents KIT- or PDGFRA-mediated signaling. Some mutations in the kinase domain apparently alter the shape of the binding site and prevent Gleevec from binding. The key (Gleevec) no longer fits into the lock (the ATP binding site in the kinase domain), and resistance to Gleevec develops.

Dr. Michael Heinrich at Oregon Health & Sciences University and others reported that of 112 GIST tumors studied, none had more than one activating mutation in KIT or PDGFRA prior to starting Gleevec. Several different groups of researchers are now reporting that many resistant tumors have a secondary mutation as well as the original primary mutation.

Dr. Lei Chen and others at M.D. Anderson Cancer Center in Houston have identified a secondary mutation that occurs in KIT kinase domain 1 (exon 13). This secondary mutation correlates with resistance to Gleevec.

Among the 130 patients in the M.D. Anderson study, 12 who had an excellent initial response were chosen for further study. Seven of these patients originally had exon 11 mutations and five had exon 9 mutations. Five of these patients developed resistance in a total of six tumors. In each case, in addition to the original exon 11 or exon 9 mutation, a new secondary exon 13 mutation, Val654Ala, was identified. In each of these cases, the secondary mutation was identical and the resistant tumors now contained both the primary mutation (exon 11 or exon 9) and the new exon 13 mutation. In the seven patients who did not develop resistance no secondary mutations were found.

Dr. T. Wakai and others of Niigata University Graduate School in Niigata City, Japan, recently published a short article identifying a patient who developed a second KIT mutation in exon 17 (the tyrosine kinase domain 2). This secondary mutation was not present in the primary tumor and resulted in Gleevec resistance in the tumor with the secondary mutation.

Dr. George Demetri of Dana-Farber and others reported early results of the SU11248 trials at the 2004 ASCO meeting. In 57 patients with Gleevecresistant GIST:
• 22 (39 percent) had a mutation in KIT only
• 1 (2 percent) had a mutation in PDGRFA only
• 9 (16 percent) had no detectable mutations (wild type)
• 25 (44 percent) had two or more mutations in KIT

Despite being resistant to Gleevec, many of the tumors with two or more KIT mutations did respond to SU11248 with either shrinkage defined by RECIST criteria or stable disease lasting more than six months thus far. Of those tumors with a secondary KIT mutation in exon 13 or exon 14, nine patients (56 percent) received benefit (response + stable > 6 months) and two patients (13 percent) achieved shrinkage. Secondary mutations in exon 17 were less sensitive to SU11248, but three patients (38 percent) still achieved stable disease for more than six months. No RECIST response occurred in the seven patients with secondary exon 17 mutations.

n his ASCO presentation, Dr. Demetri speculated on why SU11248 might work when Gleevec fails:
• SU11248 could interact differently with structural variants of new kinase mutants in GIST clones resistant to Gleevec.
• The simultaneous inhibition of multiple signaling pathways by SU11248 may be important for controlling GIST (such as VEGF, in addition to KIT and PDGFRA).

Dr. Jayesh Desai of Dana-Farber reported on a novel pattern of clonal evolution in certain GIST tumors at the 2003 Connective Tissue Oncology Society (CTOS) meeting in Barcelona, Spain. This pattern was termed a “nodule within a mass,” and was noted in approximately half of patients (22 of 42) with progressive GIST in a study by the Dana-Farber team.

These “nodules” often appeared before the development of progressive disease. Conventional tumor measurements will not detect this type of progression unless expansion of the nodule causes a very significant increase in the size of the surrounding mass. The nodule within a mass is a subtle but important early marker of GIST progression, according to Desia.

Multiple small nodules developed in some patients over a period of months. In most patients, the nodule arose from the edge of the mass, whereas both the mural surface and the tumor matrix were involved in a subset of patients.

In an interview at the 2003 CTOS meeting, Desai indicated that the keys to finding these nodules early were education and awareness of this pattern. He indicated that a high index of suspicion was needed for subtle changes like these that may develop on imaging studies. Desai went on to explain “… patients’ imatinib dose was adjusted if they had conventional indications of GIST progression, such as a new site of disease.

However, dose escalation did not seem to affect these specific nodules, which clinically, at least, appear to represent new clones of resistant disease.

If local treatments can be utilized, such as radiofrequency ablation or surgical resection of the limited resistant clone, I would give consideration to that approach. Continuation of the imatinib to maintain control of the remainder of the sensitive disease is also critical. These nodules appear to be indicative of a very limited and focal progression of disease; therefore, I would manage such individual cases following the same principles as I would a limited clonal mass that arose de novo elsewhere.”

The novel, and sometimes subtle, pattern of GIST progression present challenges. This is an important reason to have GIST experts involved in the management of GIST patients. GIST experts are not only going to be better at detecting progression, they are also generally more knowledgeable about the various treatment options after progression. Some of these options might include surgery or radiofrequency ablation for limited progression (resistant clones, etc), continuation of Gleevec to maintain control of sensitive disease, a dose increase in some cases, or referral for a clinical trial. Newer drugs might be effective in Gleevec-resistant GIST by several different methods including:
• A different shape might “fit” better into the ATP binding site in the kinase domain of tumors containing secondary mutations, or kinase domain resistant tumors.
• Inhibiting multiple targets, such as KIT and VEGF, or Src.
• Inhibiting critical downstream targets.