Overcoming treatment resistance in GIST patients

By Dr. Jonathan A. Fletcher
Department of Pathology
Brigham and Women's Hospital
Boston, Mass.

Note: Dr. Jonathan Fletcher is a member of the LRG Research Team working to understand and overcome GIST treatment resistance. This is the first article in a series to be written by each of the key research team members. In September 2006, Dr. Fletcher was presented with the LRG’s first Researcher of the Year Award by Dr. Daniel Vasella, Chief Executive Officer of Novartis, at a meeting of the Life Raft Group in Dallas, Texas. He is considered by the LRG to be the lead coordinator of the research team.

Most GISTs are “driven” by mutations of the KIT or PDGFRA genes. The mutant KIT or PDGFRA genes produce activated receptor tyrosine kinase proteins, and the activated proteins send signals into the GIST cells, directing the cells to grow. In fact, these activated proteins are largely responsible for causing GISTs to develop from normal cells in the first place. 

Dr. Jonathan Fletcher presents LRG Research Team goals at Life Fest 2006.

Most patients with GIST have their lives prolonged and suffering ameliorated using first-line treatment with imatinib mesylate (Gleevec™) which binds directly to the mutant KIT and PDGFRA proteins and inhibits their activity (1;2). The striking clinical responses to imatinib fully validate the essential oncogenic role served by KIT and PDGFRA in GISTs. Notably, KIT activation is not just essential to the development of GISTs, but actually plays an initiating oncogenic role in a subset of patients (3-5). It is not surprising, therefore, that kinase-targeting therapy with imatinib has profound effects on GIST viability, given that most GIST cells depend on an uninterrupted chain of signals emanating from the constitutively activated KIT or PDGFRA proteins. Unfortunately, even patients with nearly complete clinical responses can develop resistance to imatinib, as manifested by clinical progression of GIST. Such clinical progression typically occurs after a median of approximately 18 to 24 months after the start of imatinib therapy. The alternate small molecule therapeutic, sunitinib malate (Sutent™) which inhibits a broader spectrum of tyrosine kinase signaling proteins, can induce clinical disease control and prolong survival for patients when given second-line following failure of imatinib (6), but many patients with imatinib-resistant GIST do not benefit from sunitinib. Given that few patients have a complete response to imatinib, it is possible that most patients with metastatic GIST will ultimately develop imatinib resistance mechanisms. Several studies have shown that the dominant imatinib resistance mechanisms vary from patient to patient, and that resistance mechanisms can also vary between different metastatic lesions in a given patient (7-9).

KIT oncogenic exon 11 mutations, which are found in approximately 75 percent of GISTs, abrogate juxtamembrane region autoinhibition of the KIT kinase. Virtually all of these KIT exon 11 mutants are highly sensitive to imatinib, and patients with such mutations have better than an 80 percent clinical response rate to imatinib (10;11). At time of clinical progression on imatinib, most GIST patients with “primary” KIT juxtamembrane mutations will demonstrate additional mutations in the kinase domain (7-9;12). These kinase domain mutations are found on the same “alleles” (i.e. the same copies of the KIT gene) as the primary exon 11 mutants, and are presumably present in a small percentage of cells in the untreated GISTs – providing a selective advantage to those cells during imatinib therapy, rather than arising, de novo, as a complication of imatinib. Some of these secondary kinase domain mutations are intrinsically imatinib-resistant, as is the case with the frequently-encountered V654A mutation. However, other secondary kinase domain mutations, including those involving the activation loop N822 residue, are intrinsically imatinib-sensitive, but endow resistance when coupled with a KIT juxtamembrane region mutant, perhaps due to hyperactivation and structural changes in the KIT oncoprotein (7).

The major challenge in confronting imatinib (and sunitinib) resistance mutations clinically is the apparent heterogeneity of such mutations that can be identified amongst individual GIST patients. This clinical reality suggests that although newer generations of broad-spectrum, increasingly potent, KIT/PDGFRA kinase inhibitors will benefit patients progressing on imatinib therapy, such drugs – on their own – are unlikely to cure many patients with imatinib-resistant disease. Therefore, novel therapeutic paradigms are needed urgently, including those whose success is less dependent on the specific mutational mechanisms of KIT/PDGFRA activation. One such approach involves inhibition of the KIT chaperone, HSP90. This strategy, in preliminary studies, was particularly effective against the hyperactivated KIT oncoproteins containing imatinib-resistance mutations (13). Clinical trials of HSP90 inhibitors have begun recently at Dana-Farber Cancer Institute, but much work undoubtedly remains to determine the most effective ways of administering these promising drugs. Another clinical strategy, in patients with imatinib-resistant GIST, might involve transcriptional repression of the KIT oncogenes, as can be accomplished experimentally using flavopiridol (14), and where the presence of imatinib-resistant mutations would appear to be irrelevant to therapeutic efficacy.  Still another strategy for imatinib-resistant GIST is drug targeting of intermediate waypoints in the growth-promoting cell communication pathways regulated by KIT and PDGFRA oncoproteins. For example, the kinase proteins PI3-K and AKT seem to play crucial roles in translating KIT activation signals into GIST cell growth and survival: these “downstream” kinase proteins continue to be activated and important in GISTs that have developed imatinib and sunitinib resistance (7;15). Clinical trials of the AKT inhibitor, Perifosine, are ongoing at MD Anderson Cancer Center, and one expects that additional trials will commence once effective and selective PI3-K inhibitors – whose development is an extremely active effort at many pharmaceutical companies – are available for testing. These and other observations suggest a scenario in which patients will benefit ultimately from combinations of GIST therapies that biochemically inactivate KIT and PDGFRA (e.g. imatinib, sunitinib, nilotinib, and others), destroy KIT and PDGFRA (e.g. HSP90 inhibitors), block the production of KIT and PDGFRA (e.g. flavopiridol), and block the ability of KIT and PDGFRA to send their activating signals into the cells (e.g. AKT and PI3-K inhibitors).

In all, the complexity and heterogeneity of imatinib-resistance mutations can seem a daunting clinical challenge, but the good news is that this challenge is being met head-on by many GIST research groups and with expectations of success. New therapeutic approaches are certainly in order, and several such are already in the works, with others to follow in the next few years. Combinations of targeted therapies should ultimately serve the goal of fully shutting down KIT and PDGFRA oncogenic signaling pathways in GIST, thereby transitioning the dramatic successes of imatinib more routinely into long-term GIST control and cure.

References:

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