Glimmer of hope for imatinib-resistant GIST

The monoclonal antibody SR1 can significantly inhibit gastrointestinal stromal tumor (GIST) cell growth, report researchers in the Proceedings of the National Academy of Sciences.

The antibody targets receptor tyrosine kinase CS117 (KIT), the same receptor targeted by imatinib, and produces a similar in vitro response in cells from both drug-resistant and non-resistant tumors.

Irving Weissman (Stanford University, California, USA) and colleagues suggest that SR1 could become a future alternative or supplementary therapy for those patients who develop resistance to imatinib treatment.

The researchers tested the monoclonal antibody in vitro on two GIST cell lines resistant to imatinib, one GIST cell line unexposed to imatinib, and a control cell line from human leiomyosarcoma (LMS).

After 9-day culture, cell growth was significantly reduced in all GIST cell lines compared with control immunoglobulin G (IgG) culture. By comparison, no effect was seen in the LMS cell line. SR1-treated GIST cells also had lower levels of cell-surface KIT expression than did control-treated cells.

The authors also found that SR1 treatment of GIST cells, but not LMS cells, significantly increased their susceptibility to macrophage phagocytosis compared with untreated cells.

Additionally, mice treated for 8 weeks with SR1 had a rate of tumor growth that was a 10th of that observed in control-treated mice after injection with cells from one of the imatinib-resistant GIST lines.

Weissman and colleagues say that imatinib was a "significant milestone" in the treatment of GIST and has greatly increased the life expectancy of patients. However, resistance has limited its long-term efficacy.

"A new mutation almost always occurs over time in KIT that renders the tumor insensitive to the drug," they explain.

Other alternatives to imatinib have been hindered by low efficacy and side effects. But Weissman and colleagues believe their results signal optimism for the future treatment of GIST, as well as other cancers.

"Although this report focused on treatment of GIST cells, SR1 or other anti-KIT [monoclonal antibody] treatment may prove useful in other KIT-positive tumors, such as pancreatic adenocarcinoma, testicular seminoma, melanoma, neuroblastoma, and breast cancer," they conclude.

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