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Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

Secord, Angeles Alvarez MD, MHSc*; Teoh, Deanna MD*; Jia, Jingquan; Nixon, Andrew B.; Grace, Lisa*; Adams, David J.; Murphy, Susan K. PhD*

International Journal of Gynecological Cancer: February 2014 - Volume 24 - Issue 2 - p 218–225
doi: 10.1097/IGC.0000000000000056
Basic Science

Purpose: This study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.

Methods: Cells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.

Results: In the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%–33%; P = 0.002 to 0.04) and p-paxicillin (6%–19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49–0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).

In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49–2.27).

Conclusions: Dasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.

*Division of Gynecologic Oncology, †Departments of Medicine, and ‡Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC.

Address correspondence and reprint requests to Angeles Alvarez Secord, MD, MHSc, DUMC 3079, Division of Gynecologic Oncology, Duke University Medical Center, Erwin Road, 27710, Durham, NC 27710. E-mail: secor002@mc.duke.edu.

This study was supported by the National Cancer Institute grant supporting the Duke Clinical Oncology Research Career Development Award (K12 CA100639), a research grant from Bristol-Myers Squibb, and an anonymous philanthropic research fund.

One author has received funding from Bristol-Myers Squibb, GlaxoSmithKline, Sanofi-Aventis, and Genentech for clinical trials. She has also served on an advisory board for (<$5000 annually) Genentech. Another author received funding from Bristol-Myers Squibb. The remaining authors declare no conflicts of interest.

Received October 7, 2013

Received in revised form November 2, 2013

Accepted November 11, 2013

© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.