Clinical Management of GIST

Helsinki and Barcelona 2003-Conference Highlights

Question: Your study is entitled “Differential Gene Expression Profiles of Imatinib-Sensitive and -Resistant Sarcoma Cell Lines After Exposure to Imatinib.” Could you briefly summarize your key findings?

Dr. Trent: Our overall rationale was to identify which genes are implicated in the sensitivity of GIST cells to imatinib. After GIST cells were treated with imatinib for 24 or 48 hours, we found that 44 genes underwent a greater than two fold change in expression. Thus, we identified 44 genes that were differentially regulated actively in the imatinib-sensitive cells. The genes of particular interest to us were those related specifically to proliferation, survival, metastasis, and angiogenesis. Of the 44 genes, the ones that seemed most likely to be involved in those pathways included:

Genes that were up-regulated, such as:

  • insulin-like growth factor binding protein 3
  • protein-tyrosine phosphatase receptor type K
  • receptor interacting serine threonine kinase 2
  • tumor necrosis factor α induced protein 3\

Genes that were down-regulated, such as:

  • cathepsin L
  • cyclin D3
  • tissue inhibitor of metalloproteinase 3
  • KIT
  • several of the cytochrome C subunits
  • The gene for PDGFA also was down-regulated

Imatinib-resistant GIST cells showed less than a one fold change in expression of any of these genes after imatinib treatment.

Question: You concluded from your results that imatinib specifically modulates the transcription of genes involved in controlling the cell cycle and apoptosis, providing supporting evidence for the involvement of these pathways in the antitumor activity of the drug. Are there additional conclusions or lines of inquiry stemming from your results?

Dr. Trent: We’ll next determine which of the 44 differentially regulated genes are required for imatinib activity in GIST. If imatinib is targeting a certain subset of genes in the GIST model, then perhaps targeting similar genes in other sarcomas—or other cancers—using either 1 drug or multiple drugs may help in the development of effective therapy.

Question: KIT and PDGFRα are known targets in GIST. Is your work aimed at finding new gene targets?

Dr. Trent: KIT and PDGFRα signaling is inhibited by imatinib, and then that inhibition has an effect on the genes that are expressed in the cell. The 44 genes we identified are altered after inhibition of KIT signaling. Again, if one wanted to develop a new therapy for a different type of cancer, then the objective might be to target those same genes or similar genes. The therapy might inhibit EGFR and human epidermal growth factor receptor (HER)-2/neu together, or some combination of 3 or 4 molecules might be targeted by 3 or 4 different drugs. But the net effect may need to be inhibition or altered regulation of the same genes whose expression we found to be changed after GIST cells were treated with imatinib.

Question: Can you expand on possible implications relevant specifically to resistance?

Dr. Trent: One of the down-regulated genes was cyclin D3. That is, treatment of GIST cells with imatinib resulted in decreased expression at the RNA and protein levels of cyclin D3. The functional result is that cells stop growing and dividing, since cyclin D3 is required for proliferation. If GIST cells become resistant to imatinib, cyclin D3 may increase, and tumor cells will start proliferating again. In resistant GISTs, one might be able to target cyclin D3 using a new therapy that reduces cyclin D3 levels and restores inhibition of proliferation. There are drugs in development that are targeting cyclins. This is just one example of a potential intervention. Understanding how imatinib works in GIST will help us understand not only the cancer biology involved but also how to develop new therapeutic agents for GISTs and other sarcomas.