Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts

Abstract

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.

TGF-β-Induced TMEPAI Promotes Epithelial–Mesenchymal Transition in Doxorubicin-Treated Triple-Negative Breast Cancer Cells via SMAD3 and PI3K/AKT Pathway Alteration

“…Reduced sensitivity of cancer cells to doxorubicin can be shown by dysregulation of apoptotic marker expressions. 8 , 42 , 43 Our RT-PCR analysis suggested that doxorubicin might have a weaker pro-apoptotic activity in TMEPAI positive cells than knock-out cells. However, we acknowledge that a better correlation to apoptotic markers will be achieved if we analyze using Western blotting.…”

“… 2 , 5–7 Despite the benefit of systemic chemotherapy in improving outcomes of TNBC patients, the problem with chemoresistance is significant, which accounts for about 90% of treatment failure cases. 8–11 …”

Synthesis and Biological Evaluation of Furyl-Carboxamide Derivatives as Potential Anticancer Agents

“…The concentrations at which cell growth is inhibited by 50% (GI50) after 72 hrs exposure of cells to furyl carboxamide derivatives 3, 5, 7, and Doxorubicin were obtained from dose-response curves after considering the initial optical density acquired at the time of treatment. GI50 values are presented in Table 1, while Figure 1 shows the structure of Doxorubicin as a reference drug used as an antiproliferation-active compound (12). As can be deduced from the table, the three compounds 3, 5, and 7 show significant and almost identical cellular growth inhibitory activity against human carcinoma colon HCT-116 cell line in the examined concentration range (0.01-100 μM).…”

In Vitro Evaluation of NLS-DTX Activity in Triple-Negative Breast Cancer

“…Commercially available cancer drugs exhibit a variety of systemic toxic effects, due to many factors including high toxicity, low bioavailability, high drug dispersion in the body, and absence of drug delivery and controlled release devices [ 8 ]. The standard chemotherapy against TNBC is based on an anthracycline-taxane combination, but a significant proportion (30–40%) of patients with early-stage TNBC develop metastatic disease and succumb to cancer, so some modifications in the traditional TNBC chemotherapy regimens are necessary [ 9 , 10 ].…”