Abstract P5-08-17: Small G protein RALA is a driver and potential therapeutic target in triple negative breast cancer

Abstract Triple Negative Breast Cancer (TNBC) is the leading cause of cancer mortality in women, mostly due to the lack of targeted treatment for this subtype of breast cancer (BC). RALA and RALB are small GTPases implicated in tumor proliferation, survival, and metastasis in a variety of cancers. However, little is known of their roles in breast cancer. Utilizing 3D spheroid invasion assays, we identified that knockout (KO) of RALA greatly reduced the invasion of MDA-MB-231 spheroids in basement membrane extract (BME). Conversely, RALB-KO significantly increased 3D invasion of MDA-MB-231 cells. We further investigated roles for RALA and RALB in TNBC with cell viability assays, transwell assays, and 3D growth assays. Results indicate that KO or depletion of RALA in TNBC cell lines MDA-MB-231 and MDA-MB-468 reduces cell viability and cell migration capabilities in vitro. On the contrary, loss of RALB increased cell migration and viability. Treating TNBC cells with a small molecule inhibitor of both RAL isoforms (BQU57) reduced cell growth in vitro as well as tumor growth and metastasis in vivo. Furthermore, RALA expression, but not RALB expression, was predictive of response to chemotherapy in TNBC patients and RAL inhibitor sensitized TNBC cells to paclitaxel. Combined, these results highlight the importance of the RALs, particularly RALA, as a therapeutic targets in TNBC. Citation Format: Dillon S. Richardson, Matthew W. Cole, Rachel E. Schafer, Jonathan M. Spehar, Sarah A. Steck, Manjusri Das, Arthur W. Lian, Alo Ray, Reena Shakya, Sue E. Knoblaugh, Cynthia D. Timmers, Gina M. Sizemore, Steven T. Sizemore. Small G protein RALA is a driver and potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-17.