Abstract A265: L-methionine restriction sensitizes triple-negative breast cancer cells to a TRAIL receptor-2 agonist by reducing the expression of the melanoma-associated antigen MAGE-D2.

Abstract

Abstract The prognosis for most women with metastatic breast cancer remains poor due to a dearth of effective adjuvant therapies for this advanced stage of the disease. We have previously demonstrated that targeting TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) suppressed metastases in a murine model of triple-negative breast cancer (TNBC). However, many TNBCs are resistant to TRAIL receptor agonists. Restriction of the essential amino acid L-methionine has been reported to inhibit growth of transformed cells in preclinical models. We postulated that methionine restriction would sensitize TNBC cells to TRAIL-R2 agonists such as the humanized monoclonal antibody lexatumumab. Here we demonstrate that methionine restriction sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis. Intriguingly, methionine restriction also sensitized transformed MCF10A-RasV12 cells, but not untransformed MCF10A-Vector cells, to lexatumumab. Methionine restriction enhanced the cell surface expression of TRAIL-R2. To delineate the underlying mechanism(s), we performed proteomics analyses of TNBC cells grown in methionine restricted media and observed that methionine restriction dramatically reduced the expression of the melanoma-associated antigen MAGE-D2, which has recently been reported to inhibit TRAIL-R2 expression. siRNAs targeting MAGE-D2 mimicked the actions of methionine restriction by augmenting cell surface expression of TRAIL-R2 and sensitizing TNBC cells to lexatumumab. Overall, our results demonstrate that methionine restriction sensitizes TNBC cells to TRAIL-R2 agonists and suggest that dietary methionine restriction may be a strategy to augment the antitumor effects of TRAIL receptor agonists in vivo. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A265. Citation Format: Elena Strekalova, Dmitry Malin, David Good, Vincent Cryns. L-methionine restriction sensitizes triple-negative breast cancer cells to a TRAIL receptor-2 agonist by reducing the expression of the melanoma-associated antigen MAGE-D2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A265.