Muñoz-Galván, SandraFelipe-Abrio, BlancaGarcía-Carrasco, MiguelDomínguez-Piñol, JuliaSuarez-Martinez, ElisaVerdugo-Sivianes, Eva M.Espinosa-Sánchez, AsunciónNavas, Lola E.Otero-Albiol, DanielMarin, Juan J.Jiménez-García, Manuel P.García-Heredia, Jose M.Quiroga, Adoración G.Estevez-Garcia, PurificacionCarnero, Amancio2020-08-242020-08-242019-06-03Muñoz-Galván S, Felipe-Abrio B, García-Carrasco M, Domínguez-Piñol J, Suarez-Martinez E, Verdugo-Sivianes EM, et al. New markers for human ovarian cancer that link platinum resistance to the cancer stem cell phenotype and define new therapeutic combinations and diagnostic tools. J Exp Clin Cancer Res. 2019 Jun 3;38(1):234.http://hdl.handle.net/10668/3169Background: Ovarian cancer is the leading cause of gynecologic cancer-related death, due in part to a late diagnosis and a high rate of recurrence. Primary and acquired platinum resistance is related to a low response probability to subsequent lines of treatment and to a poor survival. Therefore, a comprehensive understanding of the mechanisms that drive platinum resistance is urgently needed. Methods: We used bioinformatics analysis of public databases and RT-qPCR to quantitate the relative gene expression profiles of ovarian tumors. Many of the dysregulated genes were cancer stem cell (CSC) factors, and we analyzed its relation to therapeutic resistance in human primary tumors. We also performed clustering and in vitro analyses of therapy cytotoxicity in tumorspheres. Results: Using bioinformatics analysis, we identified transcriptional targets that are common endpoints of genetic alterations linked to platinum resistance in ovarian tumors. Most of these genes are grouped into 4 main clusters related to the CSC phenotype, including the DNA damage, Notch and C-KIT/MAPK/MEK pathways. The relative expression of these genes, either alone or in combination, is related to prognosis and provide a connection between platinum resistance and the CSC phenotype. However, the expression of the CSC-related markers was heterogeneous in the resistant tumors, most likely because there were different CSC pools. Furthermore, our in vitro results showed that the inhibition of the CSC-related targets lying at the intersection of the DNA damage, Notch and C-KIT/MAPK/MEK pathways sensitize CSC-enriched tumorspheres to platinum therapies, suggesting a new option for the treatment of patients with platinum-resistant ovarian cancer. Conclusions: The current study presents a new approach to target the physiology of resistant ovarian tumor cells through the identification of core biomarkers. We hypothesize that the identified mutations confer platinum resistance by converging to activate a few pathways and to induce the expression of a few common, measurable and targetable essential genes. These pathways include the DNA damage, Notch and C-KIT/MAPK/MEK pathways. Finally, the combined inhibition of one of these pathways with platinum treatment increases the sensitivity of CSC-enriched tumorspheres to low doses of platinum, suggesting a new treatment for ovarian cancer.enOvarian cancerCancer stem cellsBiomarkersTherapyOvarian neoplasmsNeoplasias ováricasNeoplastic stem cellsCélulas madre neoplásicasBiomarcadoresTerapéuticaMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic AgentsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy ProtocolsMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, NeoplasmMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Survival Analysis::Kaplan-Meier EstimateMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Molecular Diagnostic TechniquesMedical Subject Headings::Anatomy::Cells::Stem Cells::Neoplastic Stem CellsMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian NeoplasmsMedical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Elements::Metals, Heavy::PlatinumMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::PrognosisMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Proportional Hazards ModelsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment OutcomeMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeuticsresearch article31159852open access10.1186/s13046-019-1245-51756-9966PMC6547556