Abstract P3-05-08: Sortilin-related receptor regulates receptor tyrosine kinase traffic and signaling

Understanding the mechanisms of resistance to targeted therapies is a major challenge in epidermal growth factor receptor 2 (ERBB2)-amplified breast cancer and acquired resistance to ERBB2 inhibition is a common feature of recurrent tumors. In such a setting, the activation of intracellular oncogenic signaling pathways, through alternative growth factor receptors, adds a layer of complexity to therapeutic options. Our aim is to scrutinize the intracellular retrograde transport of ERBB-family receptors and to assess whether the key sorting proteins involved within this pathway represent a potential vulnerability in ERBB2-amplified breast cancer. Sortilin-related receptor (SorLA; SORL1) is a vacuolar protein sorting 10 (VPS10)-domain receptor well characterized for its role in Alzheimer’s and metabolic diseases. In a previous study, we demonstrated a previously unknown role of SorLA in cancer. SorLA increases ERBB2 stability by stimulating its recycling from endosomes back to the plasma membrane thus sustaining ERBB2 oncogenic signaling in vitro. In an orthotopic xenograft model, SorLA silencing inhibits tumor growth adding translational relevance for SorLA targeting in breast cancer. Here we investigate possible crosstalk inputs from other growth factor receptors, and we evaluate the potential of SorLA inhibition as a unique strategy to halt the progression of ERBB2-amplified tumors. Citation Format: Hussein Al Akhrass, James Conway, Mark Barok, Olav Andersen, Johanna Ivaska. Sortilin-related receptor regulates receptor tyrosine kinase traffic and signaling [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-08.