title: Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance.
abstract: Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093; Laboratory of Neuropathology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan;
authors.forename: Kenta
authors.initials: K
authors.lastname: Masui
authors.affiliation: Department of Neurosurgery, Kobe University, Kobe 650-0017, Japan;
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093;
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegami
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093;
authors.forename: Genaro R
authors.initials: GR
authors.lastname: Villa
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093;
authors.forename: Huijun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Henry Singleton Brain Tumor Program, David Geffen UCLA School of Medicine, Los Angeles, CA 90095; Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, CA 90095;
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Henry Singleton Brain Tumor Program, David Geffen UCLA School of Medicine, Los Angeles, CA 90095; Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, CA 90095; Department of Neurology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095;
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan;
authors.forename: Kanato
authors.initials: K
authors.lastname: Yamagata
authors.affiliation: Laboratory of Neuropathology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan;
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Arai
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; pmischel@ucsd.edu wcavenee@ucsd.edu.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; Department of Pathology, University of California San Diego, La Jolla, CA 92093 pmischel@ucsd.edu wcavenee@ucsd.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000085:Acetates / Q000737:chemistry; D000105:Acetyl Coenzyme A / Q000737:chemistry; D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000737:chemistry*; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000085:Acetates; D000105:Acetyl Coenzyme A; D002352:Carrier Proteins; D066246:ErbB Receptors; D005947:Glucose; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases; C492571:RICTOR protein, human; C494918:AKT1 protein, human
keywords: Rictor acetylation; glioblastoma; mTORC2; metabolic reprogramming; targeted therapy resistance