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Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells.

Abstract：

BACKGROUND:Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule-stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC. METHODS:Representative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44(+) and CD24(-/low), or Aldefluor(+)) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro. RESULTS:Although there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p <0.0001), when compared to Ixabepilone alone. CONCLUSIONS:Overall, our findings demonstrate that EGFR-targeted therapy by Cetuximab effectively reduces the CSC population in TNBC tumors. However, combination therapy with Ixabepilone may be effective only in a small subset of TNBCs, warranting further investigation of alternative approaches to target multiple pathways for TNBC treatment.

journal_name

Breast Cancer Res

journal_title

Breast cancer research : BCR

authors

Tanei T,Choi DS,Rodriguez AA,Liang DH,Dobrolecki L,Ghosh M,Landis MD,Chang JC

doi

10.1186/s13058-015-0662-4

subject

Has Abstract

pub_date

2016-01-12 00:00:00

pages

issue

eissn

1465-5411

issn

1465-542X

pii

10.1186/s13058-015-0662-4

journal_volume

pub_type

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Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells.