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

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.

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

“…G-963 was active in 39% of the lines in a panel of 31 NSCLC cell lines, with cellular IC 50 values ranging from 3 to 600 nmol/L. The majority of responsive cell lines (IC 50 < 1 mmol/L) harbored activating mutations in EGFR or KRAS (Table 1), consistent with reports that activating KRAS mutations generally correlate with greater sensitivity to single-agent MEK inhibition (32)(33)(34)(35). To evaluate the potential benefit of combining an MEK inhibitor and a Bcl-2/Bcl-x L inhibitor, we employed a dose matrix to sample a large range of concentrations and concentration ratios and analyzed combination effects using the Bliss independence model.…”

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

“…Notably, within these genes are negative-feedback regulators of the RAS/MAPK pathway, including DUSP6, SPRY2, SPRY4, SPRED1, and SPRED2 ( Figure 2, B and C). MAPK negative-feedback regulators are dynamically regulated in response to MAPK signaling activity, and their expression levels are correlated with MAPK signaling output in cancer (10,11). This observation suggests that ETV1 is involved in the homeostasis of MAPK signaling through direct regulation of the negative-feedback regulators.…”

“…Cancers with constitutively activated MAPK signaling exhibit elevated ERK-dependent transcriptional output, and inhibition of this output is correlated with a therapeutic response to targeted therapies (10,11). While one characterized mode of transcriptional regulation is direct ERKmediated phosphorylation of transcription factors (12)(13)(14), other mechanisms that dynamically couple ERK activity and modulate the nuclear transcriptional output response in ERK-dependent cancers have not been elucidated.…”

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

“…153 By analyzing transcriptional pathway signatures, a panel of 18 genes has been determined to be important in terms of MEK addiction and response to the MEK inhibitor selumetinib (AZD6244, ARRY-142886). 154 Importantly, this transcriptional signature was determined to be reproducible across different cell panels of diverse tumor origins, even when the profiling was performed in different laboratories using different technology platforms. The genes they determined to be transcriptional common events to MEK function are termed MEK-functionalactivation signature and include: dual-specificity phosphatases (DUSP4/6), sprouty homologue 2 (SPRY2), pleckstrin homologylike domain family A member 1 (PHLD1), all the above three genes were previously identified to be transcriptional targets of MEK/ERK and involved in the downregulation of the pathway.…”