title: Inhibition of succinate dehydrogenase sensitizes cyclin E-driven ovarian cancer to CDK inhibition.
abstract: OBJECTIVE
  High-grade serous ovarian cancer (HGS-OvCa) is characterized by widespread CCNE1 amplification. Current treatments lack specificity to target Cyclin E-driven OvCa.
  
  
  METHODS
  By in silico analysis of the TCGA OvCa dataset we searched association between genes involved in glucose metabolism and cell cycle control. Metabolic shift was studied in Cyclin E-driven OvCa cells treated with CDK inhibition (CDKi). Genetic and pharmaceutical inhibition of succinate dehydrogenase (SDH) was tested in combination with CDKi.
  
  
  RESULTS
  OvCa patients with CCNE1 amplification could be divided by concomitant SDHA amplification. A2780 OvCa cells were similar to the Cyclin E-driven and SDHA neutral genotype. CDKi in A2780 cells using Dinaciclib resulted in compensatory enhancement of tricarboxylicacid cycle (TCA) cycle activity. Combined blockade of CDK and SDH, both genetically and pharmaceutically, showed synergy and resulted in inhibited proliferation, migration, invasion and migration in A2780 cells. The combined inhibition did not further alter cell cycle population, but induced apoptosis of A2780 cells.
  
  
  CONCLUSIONS
  Cyclin E-driven OvCa cells appeared addicted to glucose metabolism via TCA. Combined CDKi with modalities targeting TCA, like SDHA inhibition showed promising effects for this genotype.
authors.affiliation: Department of Gynaecology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Gynaecology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Gynaecology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gynaecology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Gynaecology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Gynaecology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China.
authors.forename: Congjian
authors.initials: C
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D003497:Cyclic N-Oxides; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007212:Indolizines; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011726:Pyridinium Compounds / Q000008:administration & dosage*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C475820:CCNE1 protein, human; D003497:Cyclic N-Oxides; D019927:Cyclin E; D007212:Indolizines; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; C491545:SDHD protein, human; C553669:dinaciclib; D013385:Succinate Dehydrogenase; D005947:Glucose
keywords: CDK inhibition; SDHA; cyclin E; ovarian cancer