Abstract PO3-28-11: Potassium channel activity unveils breast cancer vulnerability

Abstract

Abstract Decades of studies on ion channels have vastly demonstrated the critical functions of these proteins in many physiological and pathological conditions and have provided for an extraordinary pharmacopeia of useful compounds, often with selective actions and minimal side effects. Nevertheless, the function of ion channels in controlling cancer biology is still unknown and underexplored. Our research demonstrates that breast cancer downregulates expression of specific potassium channels (e.g., Kv11.1, KCa3.1) independently of their molecular characterization (ER+, HERB2+ and TNBC). Furthermore, breast cancer patients expressing high protein level of each of these channels presents a better overall survival when compared with patients with low expression. These data indicate that potassium channels can be prognostic factors and that high activity of these protein affects tumor growth. Therefor we wanted to understand the therapeutic benefits of pharmacological targeting specific potassium channels in breast cancer. We discovered that stimulation of the Kv11.1 with specific and selective activator molecules produced a significant growth arrest in a variety of experimental systems including in vitro, in vivo and ex vivo (e.g. Patient-derived organoids) systems. Studying the biochemical pathways that underline these events we discovered that Kv11.1 agonists affects different hallmarks of cancer including metabolism, growth and metastasis signaling without producing significant side effects. For example, use of Kv11.1 agonists produced a strong suppression of oncogene protein function including c-Myc while increasing oncosuppressors such as p21 and p16. These events associated with activation of a senescent phenotype. Furthermore, stimulation of Kv11.1 channel reversed the epithelial-to-mesenchymal transition by inhibiting the WNT signaling and reduced spreading of a TNBC by arresting the metastatic process.. Furthermore, Kv11.1 activation produced a Ca2+-dependent mitochondria damage where the antioxidant transcription factor NRF2 played a fundamental role in determining resistance to death. Therefore, we conclude that targeting the Kv11.1 potassium channel in breasts cancer can be considered a new, effective and safe targeting strategy for breast cancer. Citation Format: Saverio Gentile. Potassium channel activity unveils breast cancer vulnerability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-11.