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Mol Cancer Res. 2012 Dec;10(12):1607-19. doi: 10.1158/1541-7786.MCR-12-0188. Epub 2012 Jul 25.

Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity.

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Helen Diller Family Comprehensive Cancer Center & Department of Cell and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.

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  • Mol Cancer Res. 2013 Jun;11(6):686.


Mutationally activated KRAS, detected in approximately 90% of pancreatic ductal adenocarcinomas (PDA), has proven an intractable pharmacologic target to date. Consequently, efforts to treat KRAS-mutated cancers are focused on targeting RAS-regulated signaling pathways. In mouse models, expression of BRAF(V600E) combined with dominant-negative TP53 elicits PDA, and pharmacologic blockade of mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibits proliferation of human PDA-derived cell lines. To better understand the role of RAF→MEK→ERK signaling on PDA cell proliferation, we assessed the consequences of MEK inhibition on global patterns of mRNA expression and tumor cell proliferation in a panel of human PDA-derived cell lines. This analysis revealed that RAF→MEK→ERK signaling regulates mRNAs involved in cell-cycle control as well as regulators of the immune system. Linear regression analysis of relative drug sensitivity and mRNA expression revealed mRNAs and pathways correlating with relative drug sensitivity of the cell lines. Mice carrying orthotopically implanted pancreas tumors that were treated with MEK inhibitor displayed reduced tumor growth, concomitant with a reduction of cells in S phase. Furthermore, analysis of tumor mRNA expression revealed PDA cell lines to display similar baseline and MEK inhibitor mRNA expression profiles in vitro and in vivo. Among the proteins subject to downregulation following MEK inhibition, we identified c-MYC as a key driver of cell proliferation downstream of RAF→MEK→ERK signaling. Indeed, in some PDA cell lines, RNA interference-mediated silencing of c-MYC expression had antiproliferative effects similar to that of MEK inhibition, thereby highlighting the importance of c-MYC in key aspects of pancreatic cancer cell maintenance.

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