Study: GIST can outwit Gleevec four ways

Growing tumors share similarities, reveal likely targets for chemotherapy

While Gleevec is the most effective treatments of an uncommon leukemia and soft tissue sarcoma, it doesn’t work for everyone. U.S. researchers attending the May 31-June 3 meeting of the American Society of Clinical Oncology in Chicago reported finding four ways that GIST gets around Gleevec.

In an abstract titled “Mechanisms of resistance to imatinib mesylate [Gleevec] in advanced gastrointestinal stromal tumor (GIST)” the authors reported the following:

Based upon 16 patients resistant to Gleevec (three with initial resistance and 13 who relapsed after an initial response), the authors identified four mechanisms of Gleevec resistance:
1. Target resistance due to mutation (four relapses) evidenced by acquisition of a new KIT or PDGFRA point mutation superimposed on the pretreatment mutation in that gene, and with KIT or PDGFRA protein activation. Apparently the second (new) mutation caused the tumors to become less sensitive to Gleevec.
2. Target resistance by over expression (two relapses) evidenced by KIT genomic amplification, accompanied by over expression of the KIT oncoprotein and without acquisition of a new point mutation in the KIT gene. In these cases, no new gene mutations were found, however the cells produced more KIT protein (~4-fold over expression of KIT protein) than Gleevec was able to inhibit.
3. Target modulation (two relapses) evidenced by activation or an alternate receptor tyrosine kinase protein, accompanied by loss of KIT oncoprotein expression. In these cases, signaling from another receptor provided a new growth signal to the tumor(s) even though KIT signaling was no longer active. 4. Functional resistance (five relapses and three with initial resistance) evidenced by KIT or PDGFRA activation, in absence of a secondary genomic mutation, and with pretreatment KIT or PDGFRA mutations in six tumors (three relapse and all three with initial resistance) being outside of the juxtamembrane hot spot regions. In these cases, the gene mutations were apparently outside the exons that respond best to Gleevec (exon 11 for KIT and exon 12 for PDGFRA).

Most important, all tumors at progression demonstrated activation of similar essential downstream signaling pathways/kinases, including the AKT/ mTOR pathway, which therefore may be targeted.

The study authors were J.A. Fletcher, C.L. Corless, S. Dimitrijevic, M.Von Mehren, B.Eisenberg, H.Joensuu, C.D. M. Fletcher, C.Blanke, G.D. Demetri, M.C. Heinrich, for the GIST Working Group; Brigham and Women's Hospital, Boston, Mass.; Oregon Health Sciences University, Portland, Ore.; Novartis Oncology, Basel, Switzerland; Fox Chase Cancer Center, Philadelphia, Penn.; University of Helsinki, Helsinki, Finland; Dana-Farber Cancer Institute, Boston, Mass.