Abstract 6994: MerTK drives proliferation and metastasis activity in triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is characterized by the absence of estrogen, progesterone, and HER2 receptors. It exhibits a higher level of aggressiveness compared to other types of breast cancer, with a greater likelihood of recurrence following standard treatments such as surgery, chemotherapy, and radiation. Despite limited FDA-approved targeted therapies for TNBC, there is an ongoing need for additional molecular targeting agents. Our investigation focused on the role of the receptor tyrosine kinase MerTK and its impact on proliferation and invasion/metastatic potential. Immunohistochemistry analysis revealed that approximately 86% (128/148) expressed varying levels of MerTK in human TNBC samples, whereas approximately 50% (23/47) of TNBC patient-derived xenografts (PDX) expressed MerTK. Additionally, three established TNBC cell lines (BT549, MDAMB231, and MDAMB436) exhibited elevated MerTK expression levels. To further explore the role of MerTK in TNBC, we stably overexpressed MerTK in human TNBC cell lines SUM102 and SUM159, which naturally have low MerTK levels. The results demonstrated that MerTK overexpression led to increases in proliferative potential, robust in vivo tumor growth, heightened migration/invasion potential, and increased lung metastasis. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, including PI3k-Akt, PDGF, and Myc, ultimately driving cell cycle progression, reducing apoptosis, and enhancing cell survival in TNBC. Further investigation using a cytokine array showed increased endoglin production in SUM102-MerTK cells compared to vector control cells. This suggested that MerTK might be creating a conducive environment for increased proliferative and metastatic activity via elevated endoglin expression in TNBC. To ascertain the role of endoglin in increase proliferation and/or invasion potential, we knocked out endoglin in SUM102-MerTK cells. While endoglin knockout SUM102-MerTK cells exhibited similar growth to SUM102-MerTK cells, the number of lung metastases was significantly impacted, indicating that MerTK regulates invasion and metastasis through endoglin in TNBC. Collectively, our data suggests that MerTK regulates a unique proliferative signature allowing for robust tumor growth and increased metastatic potential through endoglin regulation. This suggests that targeting MerTK and endoglin simultaneously may be a viable approach for TNBC patients. Citation Format: Christine Glitchev, Mari Iida, Bridget E. Crossman, Kourtney L. Kostecki, Carlene A. Kranjac, Jillian M. Adams, Peng Liu, Irene Ong, David T. Yang, Irene Kang, Ravi Salgia, Deric L. Wheeler. MerTK drives proliferation and metastasis activity in triple negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6994.