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BRAF Is Associated with Disabled Feedback Inhibition of RAF–MEK Signaling and Elevated Transcriptional Output of the Pathway

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BRAF Is Associated with Disabled Feedback Inhibition of RAF–MEK Signaling and Elevated Transcriptional Output of the Pathway V600EBRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathway Christine A. Pratilasa,b, Barry S. Taylorc,d, Qing Yeb, Agnes Vialee, Chris Sanderc, David B. Solitf,g, and Neal Rosenb,f,1 Departments of aPediatrics, fMedicine, bMolecular Pharmacology and Chemistry, cComputational Biology, and eMolecular Biology, and gHuman Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and dDepartment of Physiology and Biophysics, Weill Cornell Graduate School of Medical Science, New York, NY 10065 Communicated by Samuel J. Danishefsky, Memorial Sloan-Kettering Cancer Center, New York, NY, January 28, 2009 (received for review July 18, 2008) Tumors with mutant BRAF and those with receptor tyrosine kinase pathway activation, may not be an accurate measure of pathway (RTK) activation have similar levels of phosphorylated ERK, but output. Thus, although pERK levels are similar in tumors with only the former depend on ERK signaling for proliferation. The BRAF mutation and those with RTK activation, ERK pathway mitogen-activated protein kinase, extracellular signal-regulated signaling output may be elevated only in the former. kinase kinase (MEK)/ERK-dependent transcriptional output was To address these issues, we sought to identify the genes whose defined as the genes whose expression changes significantly 8 h expression changes rapidly after MEK inhibition and that therefore after MEK inhibition. In V600EBRAF cells, this output is comprised of comprise the transcriptional output of the MEK/ERK pathway. A 52 genes, including transcription factors that regulate transforma- program of 52 genes was found to be differentially regulated after tion and members of the dual specificity phosphatase and Sprouty treatment of V600EBRAF tumor cells with a selective inhibitor of gene families, feedback inhibitors of ERK signaling. No such genes MEK. In contrast, no such set of genes was identified in a group of were identified in RTK tumor cells, suggesting that ERK pathway tumor cells with RTK activation. These data are consistent with signaling output is selectively activated in BRAF mutant tumors. elevation of ERK signaling output in MEK/ERK-dependent tu- We find that RAF signaling is feedback down-regulated in RTK cells, mors with V600EBRAF. but is insensitive to this feedback in BRAF mutant tumors. Physi- The profile of genes dependent on MEK/ERK signaling for ologic feedback inhibition of RAF/MEK signaling down-regulates expression in V600EBRAF tumor cells includes transcription factors ERK output in RTK cells; evasion of this feedback in mutant BRAF associated with ERK-dependent transformation, such as members cells is associated with increased transcriptional output and MEK/ of the ETS family, FOS and MYC. The profile also includes ERK-dependent transformation. feedback regulators of ERK signaling, several of which are mark- ͉ ͉ edly overexpressed compared with levels found in RTK-activated BRAF mutation dual specificity phosphatase mitogen-activated protein tumor cells. The increased ERK signaling output and overexpres- kinase, extracellular signal-regulated kinase kinase inhibition sion of genes that feedback-inhibit the pathway suggest that feed- PHARMACOLOGY back inhibition of RAF signaling is ineffective in V600EBRAF cells. he RAF/mitogen-activated protein kinase, extracellular signal- Consistent with this idea, in RTK-driven cells, RAF/MEK signaling Tregulated kinase kinase (MEK)/ERK signaling cascade regu- is feedback-inhibited by a MEK/ERK-dependent pathway. In con- lates multiple processes required for the proliferation and survival trast, there is no evidence for such feedback in tumors with of normal cells. Hyperactivation of the pathway results in dysregu- V600EBRAF. Thus, activation of signaling output and induction of lated cell proliferation and malignant transformation in model transformation by oncoproteins such as V600EBRAF may depend on systems and occurs commonly in human tumors. These findings their insensitivity to or evasion of normal feedback control. have led to the concept that deregulation of proliferation in malignant cells is often mediated by activation of ERK signaling. In Results human tumors, ERK activation occurs as a result of receptor Identification of a Set of 52 Genes Dependent on MEK/ERK Activity in tyrosine kinase (RTK) activation or mutations in members of the V600EBRAF Tumor Cells. In tumors, ligand-dependent or mutational RAS and RAF gene families (1, 2). RAS mutation is common in activation of RTKs or mutational activation of pathway interme- malignancy, including lung, pancreatic, and colon cancer, whereas diates such as RAS and BRAF lead to activation of ERK signaling, BRAF mutation occurs in the majority of melanomas, with lower which is associated with demonstrably high intracellular levels of frequencies in thyroid cancers and other tumors (3–7). In some pERK (15–18). However, whereas the proliferation and growth of cancers, the pathway is driven by hyperactivated growth factor V600EBRAF tumors is sensitive to inhibition of MEK/ERK signal- receptors, such as HER2 in breast cancer (8, 9) or EGFR in lung ing, tumors with RTK activation are resistant (12). Thus, high levels cancer and glioblastomas (10, 11). These findings suggest that the RAF/MEK/ERK pathway is an of pERK do not correlate with dependence of the tumor cell on attractive target for therapeutic intervention. The proliferation of MEK/ERK for proliferation. It is also possible that pERK expres- tumors with BRAF mutation is sensitive to inhibition of ERK sion is a poor measure of activation of ERK pathway signaling and signaling with selective inhibitors of MEK (12). Such agents are now in clinical trial and have antitumor activity in patients with mela- Author contributions: C.A.P., B.S.T., A.V., D.B.S., and N.R. designed research; C.A.P., B.S.T., noma (13, 14). However, against expectation, the proliferation of and Q.Y. performed research; C.A.P., B.S.T., C.S. and N.R. analyzed data; and C.A.P. and N.R. tumors in which ERK signaling is driven by RTKs is insensitive to wrote the paper. MEK inhibition (12). The authors declare no conflict of interest. These results suggest that the biologic consequences of activation Freely available online through the PNAS open access option. of ERK signaling in tumors are poorly understood. It is possible that Data deposition: The data reported in this paper have been deposited in the Gene Expression ERK output is elevated in both tumors with RTK activation and Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE10086). tumors with BRAF mutation, but that the pathway is necessary for 1To whom correspondence should be addressed. E-mail: [email protected]. proliferation only in the latter. Alternatively, the level of phosphor- This article contains supporting information online at www.pnas.org/cgi/content/full/ ylated ERK (pERK), which has been used as a surrogate marker for 0900780106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0900780106 PNAS ͉ March 17, 2009 ͉ vol. 106 ͉ no. 11 ͉ 4519–4524 Downloaded by guest on September 26, 2021 Fig. 1. Identification of the transcriptional output of the MEK/ERK pathway in V600EBRAF tumor cells. (A) The plot identifies the 52 genes (probe sets in red) significantly changed in expression upon MEK inhibition, above background (probe sets for all other genes in gray) in V600EBRAF cells (n ϭ 7), determined by SAM analysis. (B) Details of expression levels for the 52 genes (60 probe sets, rows), in each of the 7 cell lines (columns) with and without MEK inhibition (heatmap values: red ϭ increased expression, blue ϭ decreased expression). Parameters in SAM: final largest median FDR is 1.03% and ␦ cutoff is 1.505. that, in reality, the output of the pathway varies as a function of the No ERK-Dependent Transcriptional Output Profile Was Identified in mechanism by which it is driven. Tumor Cells with RTK Activation. To determine whether the tran- To address this question, we compared the ERK signaling output scriptional output of the ERK pathway is similar in tumors in which in a panel of V600E BRAF tumors (sensitive to pathway inhibition) RTKs drive the pathway, this experiment was repeated with a set with that found in a panel of tumor cell lines in which the pathway of 5 cell lines with WTBRAF and RTK activation: HER2-amplified is driven by RTKs (uniformly insensitive; Fig. S1 and ref. 12). We breast cancers (BT474, SkBr3), EGF receptor (EGFR)-amplified operationally defined the transcriptional output of the pathway as breast cancers (MDA-468), squamous cell cancer (A431), and comprising those genes whose expression changes significantly after EGFR mutant lung cancer (NCI-H1650). No genes were identified MEK inhibition. PD0325901 is a selective inhibitor of MEK1 and that were significantly altered in expression in response to MEK MEK2 kinases that rapidly abrogates ERK signaling (19). In pilot inhibition in this group of cells, although pERK was effectively studies in the melanoma cell line SkMel-28, the inhibitor caused inhibited (Fig. S3A). No new genes were identified, nor did the significant changes in the expression of genes involved in signaling genes identified in the BRAF output profile change significantly in and transcription by 2 h, which increased by8haftertreatment (SI the RTK group (Fig. S3B). This finding suggests that the transcrip- Text, Fig. S2, and Table S1). Seven cell lines with V600EBRAF tional output of the ERK pathway is significantly elevated in V600E (melanoma, SkMel-1, SkMel-5, SkMel-19, SkMel-28, and BRAF compared with RTK-activated tumor cells. This con- Malme3M; colon cancer, Colo205 and HT29) were then treated clusion was confirmed when these data were reanalyzed by a with 50 nM PD0325901 for 8 h and a paired statistical analysis nonparametric rank-order analysis (SI Text). In this analysis, the MEK output genes were randomly distributed among a ranked list [significance analysis of microarrays (SAM); see Experimental Pro- of descending gene expression change (from highest magnitude cedures and ref.
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