Editors' ChoiceCancer

Imatinib self-sabotages

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Sci. Signal.  14 Apr 2015:
Vol. 8, Issue 372, pp. ec93
DOI: 10.1126/scisignal.aab3231

Receptor tyrosine kinases promote cell proliferation and survival. Imatinib (also known as Gleevec) is a drug that inhibits the activity of the receptor tyrosine kinase KIT in gastrointestinal stromal tumors (GIST). Unfortunately, tumors often develop resistance to imatinib within few years. Li et al. found that by blocking KIT-mediated signaling, imatinib inhibits a negative feedback mechanism that in turn enables the activity of another receptor tyrosine kinase in GIST cells. A screen using conditioned medium from cDNA-transfected HEK293T cells identified members of the fibroblast growth factor (FGF) family that decreased the cytotoxicity of imatinib in GIST cell lines. FGF2 and the receptor FGFR1 were abundant at the mRNA and protein level in established and primary GIST cells. Adding an FGFR inhibitor (BGJ398) to the culture medium restored imatinib sensitivity in GIST cell lines cultured with FGF2. However, FGF2 alone did not increase the proliferation of GIST cells, and BGJ398 alone did not decrease proliferation of GIST cells, suggesting that the proliferative effect of FGF signaling occurred in response to imatinib. In both cultured cells and xenografts in mice, imatinib initially reduced the amount of phosphorylated extracellular signal–regulated kinase (ERK), but several days to a week of treatment with imatinib caused emergence of phosphorylated FGFR substrate 2 (FRS2) and a return in the amount of phosphorylated ERK. These long-term effects of imatinib were prevented in cultured cells by adding BGJ398 4 hours before cells were harvested or by knocking down FGFR1, suggesting that KIT inhibition causes feedback activation of FGFR signaling. RNA sequencing of imatinib-treated cells identified genes encoding members of the dual specificity phosphatase (DUSP) and Sprouty (SPRY) families, which inhibit growth factor-induced ERK signaling. SPRY4 expression was increased in GIST cell lines and primary GIST tissues. Knocking down SPRY2 or SPRY4 increased the amount of phosphorylated FRS2 and ERK in cells treated with imatinib in the presence of FGF2. Compared with imatinib alone, a combination therapy of imatinib and BGJ398 enhanced tumor regression in a xenograft from one KIT-mutant GIST cell line and delayed tumor regrowth after cessation of therapy in another. The findings suggest that FGFR inhibition may improve the long-term efficacy of imatinib in GIST patients.

F. Li, H. Huynh, X. Li, D. A. Ruddy, Y. Wang, R. Ong, P. Chow, S. Qiu, A. Tam, D. P. Rakiec, R. Schlegel, J. E. Monahan, A. Huang, FGFR-mediated reactivation of MAPK signaling attenuates antitumor effects of imatinib in gastrointestinal stromal tumors. Cancer Discov. 5, 438–451 (2015). [Pubmed]