Abstract 447: A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers

EGFR and/or HER2 are frequently overexpressed oncoproteins in HER2+ breast cancer, Triple Negative Breast Cancer (TNBC), and Inflammatory Breast Cancer (IBC). However, EGFR and/or HER2 targeting agents have failed to make major advances in improving survival for these cancer patients, largely because these cancers frequently develop resistance to these drugs. The identification of novel treatment strategies is critically needed. Overexpression of EGFR and/or HER2 presents a severe burden to the secretary pathway, as HER-family proteins EGFR, HER2, HER3 share conserved extracellular cysteine-rich and proline-rich repeats that form numerous disulfide bonds and control cis-trans isomerization in the protein folding processes. We demonstrated that the disulfide bond disrupting Agents (DDAs) selectively killed EGFR+ and/or HER2+ breast cancer cells in vitro and decreased tumor growth of HER2+ cancer in a xenograft mouse model. DDA-dependent anti-cancer actions resulted from downregulation of EGFR/HER2/HER3, induction of AKT dephosphorylation, and activation of Endoplasmic Reticulum (ER) stress. We also investigated a novel proteotoxic combination therapy employing DDAs and Proline Isomerase Inhibitors (PIIs) in treating breast cancers. PIIs potentiated the efficacy of DDAs in downregulating EGFR/HER2/HER3 levels and initiating ER stress, and the combination was highly synergistic in reducing EGFR+ and/or HER2+ breast cancer cell viability. Importantly, the combination of DDAs and PIIs overcame single drug resistance, significantly decreased tumor volumes and increased the survival of xenograft mice. Evidence that the drug combination was effective against metastatic breast cancer cells is also provided. Citation Format: Mengxiong Wang, Renan Ferreira, Mary Law, Elham Yaaghubi, Coy Heldermon, Ronald Castellano, Brian Law. A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 447.