Sensitivity of Glioblastomas to Clinically Available MEK Inhibitors Is Defined by Neurofibromin 1 Deficiency

Department of Neurological Surgery, University of California, San Francisco, California 94158, USA.
Cancer Research (Impact Factor: 9.33). 05/2012; 72(13):3350-9. DOI: 10.1158/0008-5472.CAN-12-0334
Source: PubMed


Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor-sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor-sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials.

17 Reads
  • Source
    • "MEK inhibitor alone significantly reduced cell growth and cyclin D1 levels in U373 but not U251 cells (both cell lines from the UCSF BTRC Tissue Core). Only combined treatment with MEK inhibitor and dual PI3K/mTOR inhibitor induced similar response in U251 cells (See et al., 2012). SNB19 cells were more resistant to 1-t-butyl carbamoyl, 7-methyl-indole-3-ethyl isothiocyanate (NB7M), paclitaxel, and dasatinib treatment than U251 cells (both cell lines from NCI-60 cell line panel) (Brard et al., 2009; Moghaddas Gholami et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: •Karyotypically distinct U251, U373, and SNB19 cell lines are of the same origin.•Changes in karyotype result in the alterations of transcriptome and proteome.•Isogenic cell lines with different karyotypes have individual drug sensitivity.•Chromosome instability should be emphasized in the evaluation of multidrug resistance.
    Gene 02/2014; 540(2). DOI:10.1016/j.gene.2014.02.053 · 2.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: With increasing knowledge of cellular networks of gene and molecular interactions, and their alterations in GBM (glioblastoma multiforme), it is now possible to apply methods of Network Pharmacology (NP) to predict candidate drug targets for this malignant brain tumor. NP requires the development of mathematical methods for network stability and perturbation analysis to identify sensitive and druggable network components, as well as computational platforms to carry out in silico simulations of therapeutic interventions. This review focuses on the three most frequently deregulated GBM pathways involving membrane receptor tyrosine kinases, p53, and Rb. Structural features of these networks that may confound targeted therapies are discussed.
    Current Drug Discovery Technologies 12/2012; 10(2). DOI:10.2174/1570163811310020005
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of an array of signaling molecules, along with the assessment of real-time cell proliferation, has been performed in U87 glioma cell line and in patients' glioblastoma established cell cultures in order to provide a better understanding of cellular and molecular events involved in glioblastoma pathogenesis. Experimental therapy was performed using a phosphatidylinositol-3'-kinase (PI3K) inhibitor. xMAP technology was employed to assess expression levels of several signal transduction molecules and real-time xCELLigence platform for cell behavior. PI3K inhibition induced the most significant effects on global signaling pathways in patient-derived cell cultures, especially on members of the mitogen-activated protein-kinase family, P70S6 serine-threonine kinase, and cAMP response element-binding protein expression and further prevented tumor cell proliferation. The PI3K pathway might be a prime target for glioblastoma treatment.
    OncoTargets and Therapy 11/2013; 6:1737-1749. DOI:10.2147/OTT.S52365 · 2.31 Impact Factor
Show more

Similar Publications


17 Reads