Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)

Citations Over TimeTop 10% of 2010 papers

Abstract

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Related Papers

• → Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence(2014)308 cited
• → Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer(2019)36 cited
• → Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells(2014)29 cited
• → Case report: response to the ERK1/2 inhibitor ulixertinib in BRAF D594G cutaneous melanoma(2022)10 cited
• → Abstract 3702: Integrated genomic and proteomic analysis identifies PTEN loss and AKT/MTOR as drivers of resistance to MEK inhibitors in NSCLC cells(2014)