title: Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.
abstract: BACKGROUND
  To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway.
  
  
  METHODS
  SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated.
  
  
  RESULTS
  Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine-docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1.
  
  
  CONCLUSIONS
  Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted.
authors.affiliation: Division of Gynecologic Oncology, Duke Cancer Institute, Durham, NC 27710 USA ; DUMC 3079, Gynecologic Oncology, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Micael
authors.initials: M
authors.lastname: Lopez-Acevedo
authors.affiliation: Division of Gynecologic Oncology, Duke Cancer Institute, Durham, NC 27710 USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Grace
authors.affiliation: Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Teoh
authors.affiliation: Division of Gynecologic Oncology, Duke Cancer Institute, Durham, NC 27710 USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Whitaker
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: East Carolina University School of Medicine, Greenville, NC 27834 USA.
authors.forename: Jingquan
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
authors.affiliation: Division of Gynecologic Oncology, Duke Cancer Institute, Durham, NC 27710 USA.
authors.forename: Angeles Alvarez
authors.initials: AA
authors.lastname: Secord
keywords: Dasatinib; Leiomyosarcoma; SRC pathway; Targeted agents; Uterine sarcoma