Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers

Cancer Discov. 2014 Sep;4(9):1062-73. doi: 10.1158/2159-8290.CD-14-0159. Epub 2014 Jun 9.

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.

Significance: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers / metabolism
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Fluorodeoxyglucose F18 / metabolism
  • Glucose Transporter Type 1 / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Targeted Therapy
  • Multiprotein Complexes / metabolism
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / metabolism*
  • Neoplasms, Nerve Tissue / diagnosis
  • Neoplasms, Nerve Tissue / drug therapy
  • Neoplasms, Nerve Tissue / genetics
  • Neoplasms, Nerve Tissue / metabolism
  • Nerve Sheath Neoplasms / diagnosis
  • Nerve Sheath Neoplasms / drug therapy
  • Nerve Sheath Neoplasms / genetics
  • Nerve Sheath Neoplasms / metabolism
  • Neurofibromin 1 / genetics*
  • Neurofibromin 1 / metabolism
  • Positron-Emission Tomography
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction* / drug effects
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Glucose Transporter Type 1
  • Multiprotein Complexes
  • Neurofibromin 1
  • Protein Kinase Inhibitors
  • Fluorodeoxyglucose F18
  • Class Ia Phosphatidylinositol 3-Kinase
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases