title: Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California 94158, USA.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: See
authors.forename: I-Li
authors.initials: IL
authors.lastname: Tan
authors.forename: Joydeep
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D025542:Neurofibromin 1 / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases