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

Abstract

BackgroundDeveloping 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.MethodsRepresentative 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.ResultsAlthough 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.ConclusionsOverall, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0662-4) contains supplementary material, which is available to authorized users.

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

“…1d and f, respectively). These results agreed with a recently reported effect of Cetuximab on the CD44 + /CD24 − population in MDA-MB-231 cells [19]. EGF treatment caused a small increase of CD44 + /CD24 − populations in SUM159PT and SUM149PT cells (Fig.…”

“…One of the reasons is the lack of specific markers predicting which patients are most likely to respond to anti-EGFR therapies [1, 2, 52–55]. Recent studies demonstrating that EGFR inhibitors reduce CSC populations in TNBC tumors [19] further highlight the importance of EGFR in the pathology of triple-negative disease and underscore the need for better markers guiding patient selection for anti-EGFR therapies. Understanding the mechanism by which EGFR activation controls CSCs is needed to maximize the clinical benefit of EGFR inhibitors in the treatment of TNBCs.…”

“…Recently, it has been reported that inhibition of EGFR signaling in SUM159PT and MDA-MB-231 TNBC cell lines using Cetuximab, an anti-EGFR blocking monoclonal antibody, reduced CD44 + /CD24 −/low and Aldefluor + cell populations, decreased mammosphere formation, and partially inhibited tumor growth in vivo in mouse xenograft models [19]. These results indicated that inhibition of EGFR signaling reduced cancer stem cell (CSC) populations and suggested that anti-EGFR therapies, in combination with chemotherapy, may be more effective in eliminating CSCs compared to chemotherapy alone in some TNBC patients.…”

“…These results indicated that inhibition of EGFR signaling reduced cancer stem cell (CSC) populations and suggested that anti-EGFR therapies, in combination with chemotherapy, may be more effective in eliminating CSCs compared to chemotherapy alone in some TNBC patients. It was further postulated that the reduction of CSC populations by Cetuximab was mediated through inhibition of autophagy [19]. However, while EGFR may regulate autophagy in a context-dependent manner, most of the published reports indicate that EGFR tyrosine kinase activity inhibits autophagy [13, 20–23].…”

RETRACTED: Silencing of Prrx1b suppresses cellular proliferation, migration, invasion and epithelial–mesenchymal transition in triple‐negative breast cancer

“…TNBC constitutes approximately 10-17% of all invasive breast carcinomas and tend to more frequently affect younger patients [1,2]. TNBC tumours are also generally larger in size, of a higher grade, present lymph node involvement at the time of diagnosis, and are biologically more aggressive [3].…”