Abstract

In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in TNBC, we established a cell line model of acquired dasatinib resistance (231-DasB). Following an approximately three-month exposure to incrementally increasing concentrations of dasatinib (200 nM to 500 nM) dasatinib, 231-DasB cells were resistant to the agent with a dasatinib IC50 value greater than 5 μM compared to 0.04 ± 0.001 µM in the parental MDA-MB-231 cells. 231-DasB cells also showed resistance (2.2-fold) to the Src kinase inhibitor PD180970. Treatment of 231-DasB cells with dasatinib did not inhibit phosphorylation of Src kinase. The 231-DasB cells also had significantly increased levels of p-Met compared to the parental MDA-MB-231 cells, as measured by luminex, and resistant cells demonstrated a significant increase in sensitivity to the c-Met inhibitor, CpdA, with an IC50 value of 1.4 ± 0.5 µM compared to an IC50 of 6.8 ± 0.2 µM in the parental MDA-MB-231 cells. Treatment with CpdA decreased p-Met and p-Src in both 231-DasB and MDA-MB-231 cells. Combined treatment with dasatinib and CpdA significantly inhibited the growth of MDA-MB-231 parental cells and prevented the emergence of dasatinib resistance. If these in vitro findings can be extrapolated to human cancer treatment, combined treatment with dasatinib and a c-Met inhibitor may block the development of acquired resistance and improve response rates to dasatinib treatment in TNBC.

Highlights

  • Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and exhibits overexpression of human epidermal growth factor receptor 2 (HER2).It accounts for approximately 15% of all breast cancer cases and patients with this form demonstrate higher rates of recurrence and shorter disease progression than those with luminal or HER2-positiveCancers 2019, 11, 548; doi:10.3390/cancers11040548 www.mdpi.com/journal/cancersCancers 2019, 11, 548 tumours [1]

  • MDA-MB-231 cells are very sensitive to growth inhibition by dasatinib (IC50 = 40 ± 1 nM) [3]

  • MDA-MB-231 cells show a significant dose dependent increase in doubling time in the presence of dasatinib, whereas the 231-DasB cells show no significant change in doubling time in response to dasatinib (Table 1)

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Summary

Introduction

Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and exhibits overexpression of human epidermal growth factor receptor 2 (HER2).It accounts for approximately 15% of all breast cancer cases and patients with this form demonstrate higher rates of recurrence and shorter disease progression than those with luminal or HER2-positiveCancers 2019, 11, 548; doi:10.3390/cancers11040548 www.mdpi.com/journal/cancersCancers 2019, 11, 548 tumours [1]. Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and exhibits overexpression of human epidermal growth factor receptor 2 (HER2). It accounts for approximately 15% of all breast cancer cases and patients with this form demonstrate higher rates of recurrence and shorter disease progression than those with luminal or HER2-positive. We have previously shown that Proto-oncogene tyrosine-protein kinase Src (Src kinase) is frequently expressed in TNBC and may be a rational therapeutic target for TNBC [3]. Src is a proto-oncogene and a member of the Src family kinases (SFKs). SFKs are non-membrane-bound tyrosine kinases consisting of nine members. Yes, Fyn and Fgr belong to the Src A family subtype

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