title: Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition.
abstract: We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a "multi-orthogonal" combination tailored to the molecular physiology associated with the target cancer genome.
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.|Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nitta
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Diahnn
authors.initials: D
authors.lastname: Futalan
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Steed
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Treiber
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Zack
authors.initials: Z
authors.lastname: Taich
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Stevens
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Wykosky
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Bob S
authors.initials: BS
authors.lastname: Carter
authors.affiliation: Departments of Pediatrics and Pathology, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Kennedy
authors.affiliation: The Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Esashi
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: Arshad
authors.initials: A
authors.lastname: Desai
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D005909:Glioblastoma / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering; D000077204:Temozolomide; D000097869:Polo-Like Kinase 1
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018797:Cell Cycle Proteins; D003606:Dacarbazine; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000077204:Temozolomide; D000097869:Polo-Like Kinase 1; C410723:epidermal growth factor receptor VIII
keywords: EGFR; EGFRvIII; glioblastoma; synthetic lethality