title: TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2.
abstract: BACKGROUND
  Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs).
  
  
  RESULTS
  We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged.
  
  
  CONCLUSIONS
  Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored.
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Venkatesan
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Personalized Cancer Treatment (CPCT), University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marlous
authors.initials: M
authors.lastname: Hoogstraat
authors.affiliation: Pepscope BV, Utrecht, The Netherlands.
authors.forename: Ester
authors.initials: E
authors.lastname: Caljouw
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Tessa
authors.initials: T
authors.lastname: Pierson
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jochem K H
authors.initials: JK
authors.lastname: Spoor
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Lona
authors.initials: L
authors.lastname: Zeneyedpour
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Hendrikus J
authors.initials: HJ
authors.lastname: Dubbink
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Lennard J
authors.initials: LJ
authors.lastname: Dekker
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Mariëlle
authors.initials: M
authors.lastname: van der Kaaij
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jenneke
authors.initials: J
authors.lastname: Kloezeman
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Lotte M E
authors.initials: LM
authors.lastname: Berghauser Pont
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Personalized Cancer Treatment (CPCT), University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nicolle J M
authors.initials: NJ
authors.lastname: Besselink
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Theo M
authors.initials: TM
authors.lastname: Luider
authors.affiliation: Pepscope BV, Utrecht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Joore
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.|Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: John W
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Martine L M
authors.initials: ML
authors.lastname: Lamfers
authors.affiliation: Center for Personalized Cancer Treatment (CPCT), University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.|Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.|Department of Neurosurgery, St. Elisabeth Hospital Tilburg, Tilburg, The Netherlands.
authors.forename: Sieger
authors.initials: S
authors.lastname: Leenstra
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000737:chemistry; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D020543:Proteome; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D014408:Biomarkers, Tumor; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D020543:Proteome; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C000595707:BCL2 protein, human; C495901:TP53 protein, human; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; C528561:navitoclax
keywords: brain tumor; genetic biomarkers; personalized medicine; resistance; small molecule kinase inhibitors