There are significant unmet medical needs among patients who have HER2+ breast cancers that have acquired resistance to targeted agents, and patients with Triple-Negative Breast Cancers (TNBCs) that lack therapeutic targets. Novel treatment strategies are needed to target these cancers. Disulfide bond Disproportionation Agents (DDAs) represent a new chemical class of anticancer drugs and show prominent anti-cancer activities both in vitro and in animal model. Blockade of breast tumor growth by DDAs is associated with downregulation of EGFR/HER2/HER3 in parallel, induction of AKT dephosphorylation, and activation of ER stress. However, it is not known how DDAs trigger cancer cell death without affecting non-transformed cells. This study aims to investigate the death pathways involved in the anti-cancer activities of DDAs, and to develop strategies that target drug resistant breast cancer and cancer metastasis. This study demonstrates that DDAs induce breast cancer cell death by activating the Death Receptor 5 (DR5) pathway. DDAs are the first compounds identified that upregulate DR5 via both transcriptional and post-transcriptional mechanisms and uniquely cause DR5 accumulation and oligomerization by altering DR5 disulfide bond pattern. This study also shows that the combination of DDAs and Tumor Necrosis Family-Related Apoptosis-Inducing Ligand (TRAIL), a natural ligand of DR5, significantly overcomes TRAIL resistance that has been encountered in clinical trials with this ligand. Furthermore, DDAs and TRAIL synergistically kill Lapatinib-resistant breast cancer and cancer metastatic cells, and that this anti-cancer effect is amplified by the overexpression of EGFR/HER2/MYC. Together, this study highlights a promising novel pharmacological approach against drug resistant cancer and cancer metastasis.

Citation Format: Mengxiong Wang. Disulfide bond disproportionation agents activates the death receptor 5 pathway to kill highly resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2493.