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10.1158/2159-8290.CD-15-1377

http://scihub22266oqcxt.onion/10.1158/2159-8290.CD-15-1377
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C4957999!4957999!27154822
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suck abstract from ncbi


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pmid27154822      Cancer+Discov 2016 ; 6 (7): 754-69
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  • Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS mutant lung cancer #MMPMID27154822
  • Kitai H; Ebi H; Tomida S; Floros KV; Kotani H; Adachi Y; Oizumi S; Nishimura M; Faber AC; Yano S
  • Cancer Discov 2016[Jul]; 6 (7): 754-69 PMID27154822show ga
  • KRAS is frequently mutated in lung cancer. Whereas the mitogen-activated protein kinase (MAPK) is a well-known effector pathway of KRAS, blocking this pathway with clinically-available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator sprouty proteins; MEK inhibition led to de-repression of SPRY4 and subsequent FGFR1-mediated re-activation of MEK and AKT. Therapeutically, the combination of MEK inhibitor and FGFR inhibitor induced cell death in vitro and tumor regressions in vivo. These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.
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