Breast cancer cells evade paclitaxel-induced cell death by developing resistance to dasatinib.
Triple negative breast cancer (TNBC), which does not express the progesterone, estrogen, or HER2/neu receptor, is aggressive and difficult to treat. Paclitaxel, a tubulin stabilizing agent, is one of the most frequently prescribed anticancer agents for breast cancers, including TNBC. Residual disease that occurs due to resistance or partial resistance of cancer cells in a tumor against anticancer agents is the most important issue in oncology. In the present study, when MDA-MB-231 cells, a TNBC cell line, were treated with 30 µM paclitaxel, a slightly higher concentration than its GI50value, for 6 days, a small number of cells with different morphologies survived. Among the surviving cells, small round cells were isolated, cloned, and named MDA-MB-231-JYJ cells. MDA-MB-231-JYJ cells were observed to be highly proliferative and tumorigenic. In addition, signal transduction molecules involved in proliferation, survival, malignancy, or stemness of cancer cells, such as c-Src, c-Met, Notch 1, c-Myc, Sox2, Oct3/4, Nanog, and E-cadherin were highly expressed or activated. While further study is required, MDA-MB-231-JYJ cells appear to have some of the characteristics of cancer precursor cells. Although MDA-MB-231-JYJ cells were isolated from the cells that survived in the continuous presence of paclitaxel, they were not resistant to paclitaxel but developed resistance to dasatinib, a Bcr-Abl and Src kinase family inhibitor. The activated state of Src and Notch 1, and the expression levels of c-Myc and cyclins in MDA-MB-231-JYJ cells were less affected than MDA-MB-231 cells by the treatment of dasatinib, which may explain the resistance of MDA-MB-231-JYJ cells to dasatinib. These results suggest that cancer cells that become resistant to dasatinib during the process of paclitaxel therapy in patients may appear, and caution is required in the design of clinical trials using these two agents.
College of Pharmacy, Korea University, Sejong 30019, Republic of Korea.
Yun-Ji
YJ
Jeong
Bioevaluation Center, Korea Institute of Bioscience and Biotechnology, Ochang 28116, Republic of Korea.
Jong Soon
JS
Kang
College of Pharmacy, Korea University, Sejong 30019, Republic of Korea.
Su In
SI
Lee
College of Pharmacy, Korea University, Sejong 30019, Republic of Korea.
Dong Min
DM
So
Bioevaluation Center, Korea Institute of Bioscience and Biotechnology, Ochang 28116, Republic of Korea.
Jieun
J
Yun
College of Pharmacy, Korea University, Sejong 30019, Republic of Korea.
Ji Young
JY
Baek
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
Sang Kyum
SK
Kim
College of Pharmacy, Korea University, Sejong 30019, Republic of Korea; Research Driven Hospital, Korea University Guro Hospital, Biomedical Research Center, Seoul 08308, Republic of Korea.
Kiho
K
Lee
College of Pharmacy, Korea University, Sejong 30019, Republic of Korea; Research Driven Hospital, Korea University Guro Hospital, Biomedical Research Center, Seoul 08308, Republic of Korea.
Song-Kyu
SK
Park
breast cancer; dasatinib; drug resistance; paclitaxel