title: ErbB3 expression predicts sensitivity to elisidepsin treatment: in vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines.
abstract: Irvalec® (elisidepsin trifluoroacetate, PM02734) is a novel marine-derived             cyclic peptide belonging to the Kahaladide family of compounds, currently in clinical             trials with preliminary evidence of antitumor activity. Previous studies have             shown a correlation between elisidepsin sensitivity and expression of the ErbB3             receptor in a panel of NSCLC cell lines. We have studied the effect of elisidepsin             on the ErbB3 pathway, characterizing the expression of all members of the ErbB             (HER) family of receptors and their main downstream signaling effectors, such             as Akt and MAPK. Interestingly, we observed a downregulation of ErbB3 upon elisidepsin             treatment that correlates with a reduction in the Akt phosphorylation levels in             the most sensitive cell lines, whereas ErbB3 levels are not affected in the less             sensitive ones. Also, we observed that the basal levels of ErbB3 protein expression             show a significant correlation with cell viability response against elisidepsin             treatment in 14 different cell lines. Furthermore, we analyzed the combination             of elisidepsin with different chemotherapeutics agents, such as cisplatin, paclitaxel             and gemcitabine, in a panel of different breast (MDA-MB-435, MDA-MB-231 and MCF7),             lung (HOP62, DV90 and A549) and colorectal cancer cell lines (DLD1 and HT29).             IC50 values for the different drugs were tested. We observed a synergistic effect             in all cell lines tested with any chemotherapeutic agent. More importantly, the             two in vitro elisidepsin-resistant cell lines (MDA-MB-231 and HOP62) presented             a synergistic effect in combination with cisplatin and paclitaxel, respectively.             These results provide a rationale for further development of these combinations             in an ongoing clinical trial.
authors.affiliation: Department of Pathology, Hospital University Vall d'Hebron, 08035                     Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Teixidó
authors.forename: Elisabet
authors.initials: E
authors.lastname: Arguelaguet
authors.forename: Berta
authors.initials: B
authors.lastname: Pons
authors.forename: Miguel
authors.initials: M
authors.lastname: Aracil
authors.forename: Jose
authors.initials: J
authors.lastname: Jimeno
authors.forename: Rosa
authors.initials: R
authors.lastname: Somoza
authors.forename: Roso
authors.initials: R
authors.lastname: Marés
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón Y Cajal
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D066247:Receptor, ErbB-4; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D003841:Deoxycytidine; D047630:Depsipeptides; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D000093542:Gemcitabine; C522358:elisidepsin; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human