Summary: SPRY2 is a purported tumor suppressor in certain cancers that promotes tumor growth and resistance to receptor tyrosine kinase inhibitors in glioblastoma. Here, we identify a SPRY2-dependent bypass signaling mechanism in glioblastoma that drives resistance to EGFR and MET inhibition. In glioblastoma cells treated with EGFR and MET inhibitors, SPRY2 expression is initially suppressed but eventually rebounds due to NF-κB pathway activation, resultant autocrine FGFR activation, and reactivation of ERK, which controls SPRY2 transcription. In cells where FGFR autocrine signaling does not occur and ERK does not reactivate, or in which ERK reactivates but SPRY2 cannot be expressed, EGFR and MET inhibitors are more effective at promoting death. The same mechanism also drives acquired resistance to EGFR and MET inhibition. Furthermore, tumor xenografts expressing an ERK-dependent bioluminescent reporter engineered for these studies reveal that this bypass resistance mechanism plays out in vivo but can be overcome through simultaneous FGFR inhibition. : The poor efficacy of receptor tyrosine kinase inhibitors in glioblastoma may stem from the ability of tumor cells to rewire signaling to maintain expression of SPRY2, a driver of glioblastoma survival. Day et al. identify combination therapies that efficiently and durably suppress SPRY2 expression to potentially treat glioblastoma more effectively. Keywords: kinase inhibitors, small-animal imaging, FRA1, glioma stem cells, bypass resistance, heterogeneity, combination therapy, extracellular signal-regulated kinase (ERK), nuclear factor k-light-chain-enhancer of activated B cells, NF-κB
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