title: Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers.
abstract: NF1 encodes a RAS GTPase-activating protein. Accordingly, aberrant RAS activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which RAS pathway components represent optimal therapeutic targets. Here, we identify mTORC1 as the key PI3K effector in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. However, we find that tumor regression requires sustained inhibition of both mTORC1 and MEK. Transcriptional profiling studies were therefore used to establish a signature of effective mTORC1-MEK inhibition in vivo. We unexpectedly found that the glucose transporter GLUT1 was potently suppressed, but only when both pathways were inhibited. Moreover, unlike VHL- and LKB1-mutant cancers, reduction of (18)F-FDG uptake required the suppression of both mTORC1 and MEK. Together, these studies identify optimal and suboptimal therapeutic targets in NF1-mutant malignancies and define a noninvasive means of measuring combined mTORC1-MEK inhibition in vivo, which can be readily incorporated into clinical trials.
  
  
  CONCLUSIONS
  This work demonstrates that mTORC1 and MEK are key therapeutic targets in NF1-mutant cancers and establishes a noninvasive biomarker of effective, combined target inhibition that can be evaluated in clinical trials.
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; and.
authors.forename: Clare F
authors.initials: CF
authors.lastname: Malone
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; and.
authors.forename: Jody A
authors.initials: JA
authors.lastname: Fromm
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; and.
authors.forename: Ophélia
authors.initials: O
authors.lastname: Maertens
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; and Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: DeRaedt
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Ingraham
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; and Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts kcichowski@rics.bwh.harvard.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Cichowski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D009380:Neoplasms, Nerve Tissue / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018317:Nerve Sheath Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D051272:Glucose Transporter Type 1; D046912:Multiprotein Complexes; D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; D019788:Fluorodeoxyglucose F18; D058543:Class Ia Phosphatidylinositol 3-Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases