The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl

Abstract

Purpose Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand (TRAIL) preferentially killed triple negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5 specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. Methods We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African American women with TNBC. Results and Conclusions Drozitumab induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15% of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist.

c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo

“…More reports have indicated remarkable diversity in the molecular characteristics of TNBC . Vimentin is identified as a mesenchymal marker for basal B TNBC, which makes epithelial cancer cells more aggressive with high motility and invasion . SUM1315MO2 and MDA‐MB‐231 belong to basal B TNBC with high expression levels of vimentin, which are highly sensitive to the c‐Src inhibitor.…”

“…24,[30][31][32] Vimentin is identified as a mesenchymal marker for basal B TNBC, which makes epithelial cancer cells more aggressive with high motility and invasion. 33,34 SUM1315MO2 and MDA-MB-231 belong to basal B TNBC with high expression levels of vimentin, which are highly sensitive to the c-Src inhibitor. By contrast, vimentin-negative TNBC cell lines HCC1937 and MDA-MB-468 have low adherent activity and cellular invasive ability (data not shown).…”

Anticancer efficacy of the hypoxia‐activated prodrug evofosfamide is enhanced in combination with proapoptotic receptor agonists against osteosarcoma

“…PARAs including drozitumab and dulanermin have been tested either alone or in combination with other agents in phase I and II clinical trials , with little clinical benefit observed to date which has led to the discontinuation of the development of PARAs in many cases . However, none of these clinical trials have examined the anticancer efficacy of PARAs against cancers in the bone such as OS.…”

“…Proapoptotic Receptor Agonists (PARAs), either as monotherapy or in combination with other agents, are generally well‐tolerated by patients with very few side effects and although phase 1/1b studies provided encouraging preliminary results, findings from randomized Phase 2 studies failed to demonstrate significant clinical benefit . Despite these clinical observations, there has been no investigation examining the anticancer efficacy of evofosfamide alone or in combination with either the Proapoptotic Receptor Agonists (PARAs) dulanermin (formerly known as Apo2L/TRAIL), or drozitumab for the treatment of osteosarcoma.…”

Death Receptors: New Opportunities in Cancer Therapy

“…T cells expressing a chimeric antigen receptor (CAR) of a TRAIL receptor single-chain antibody were capable of specific elimination of tumor cells with DR4. During interaction with tumor cells, the CAR-modified T cells were shown to trigger not only a DR4-induced apoptotic pathway, but also the mechanisms of T cell cytotoxicity [ 64 , 65 ].…”