Abstract A50: Modeling and targeting of oncogenic proteotoxic stress in drug-resistant breast cancer

Abstract

ERBB2/HER2-positive breast cancers are associated with poor prognosis, and resistance to HER2-targeted therapy (trastuzumab and lapatinib) presents a significant clinical hurdle. There are no treatment options for metastatic HER2+ BCs that have progressed on HER2-targeted therapy. At present, most of the research on therapeutic strategies in therapy-refractory Her2+ BCs focuses on resensitizing tumor cells to HER2-targeting agents. We have shown that targeting of nononcogenic vulnerabilities, specifically adaptive proteotoxic stress response, is a promising therapeutic approach in this subset of BCs (Singh N. et al, HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive. Science Signaling 2015). We showed that Her2+ BCs have specific dependence on the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway to suppress the hyperactive Her2/mTOR pathway-driven proteotoxic stress. Here, we explore the kinetics of protein homeostatic changes during the course of Her2-targeted drug therapy, and identify optimal therapeutic windows for the targeting of ERAD in the therapy-refractory Her2+ BCs. Using an integrated systems approach, we have modeled the dynamics of signaling and protein homeostasis changes in Her2+ cells during remission, resistance, and relapse phases of Her2-targeted therapy. We found that the resistance and relapse phases of anti-Her2 drug (lapatinib and trastuzumab) treatment are associated with Her2-independent acquisition of mTOR signaling, as previously reported. However, these signaling pathway changes also resulted in heightened proteotoxic burden on the ER due to increased protein synthesis rates, which was further exacerbated upon the release of cells from anti-Her2 treatment. Accordingly, cells in the relapse phase, and even more so upon further drug withdrawal, showed significantly heightened sensitivity to the inhibition of ERAD. This study reveals the kinetics of protein homeostasis associated with the signaling pathway changes during acquired resistance to anti-Her2 therapy, and suggests optimal therapeutic windows for the targeting of ERAD in therapy-refractory Her2+ BCs. Citation Format: Navneet Singh, Vishnu Modur, Belal Muhammad, Kakajan Komurov. Modeling and targeting of oncogenic proteotoxic stress in drug-resistant breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A50.