Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.

Micael Lopez-Acevedo,Andrew B Nixon,Deanna Teoh,Angeles Alvarez Secord,Jingquan Jia,Regina Whitaker,Lisa Grace,David J Adams

doi:10.1186/2053-6844-1-2

Abstract

BackgroundTo 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.MethodsSK-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.ResultsActivated 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.ConclusionDasatinib 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.Electronic supplementary materialThe online version of this article (doi:10.1186/2053-6844-1-2) contains supplementary material, which is available to authorized users.

Highlights

To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma cell lines, and determine if dasatinib inhibits the SRC pathway
In SK-UT-1, treatment with dasatinib resulted in a loss of SRC activation at 30 nm (16%; p < 0.001), 100 nm (8%; p < 0.001) and 500 nm (2%; p < 0.001) (Figure 1)
PSRC levels were significantly decreased after treatment with dasatinib at 30 nm (24%, p < 0.001), 100 nm (14%, p < 0.001) and 500 nm (3%, p < 0.001) (Additional file 3: Figure S3)

Summary

Introduction

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. Leiomyosarcomas (LMS) are a rare and aggressive type of uterine malignancy that has an extremely poor prognosis. Adjuvant gemcitabine and docetaxel was evaluated in women with completely resected stage I to IV uterine LMS. The PFS2 yrs was 45% with a median PFS of 13 months and the median survival was not yet reached [3]. Despite these modest improvements, there is an urgent need for innovative therapeutic approaches

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