Abstract B38: Exploring targeting potassium channels in cancer: A novel strategy for therapeutic intervention

Abstract

Abstract Failing of anticancer therapies is mostly due to our limited understanding of biochemical signaling in cancer cells. Therefore, identification of new targets and new strategies for anticancer drug discovery is greatly needed. Potassium ion (K+) channels are transmembrane associated proteins that control several biological processes including cell proliferation and cell motility in both physiological and pathological conditions by allowing an outward flux of K+ ion to cross the surface membrane. Furthermore, several K+ ion channels have been found expressed in cancers of different histogenesis but not in tissues from which cancer has been generated. This suggests that changes in K+ ion gradients play a key role in cancer biology. In contrast to blockers, K+ channels activators are well tolerated in mammals and several FDA approved K+ channels activators are readily available on the market suggesting that these agents could be used as potential anticancer drug. Nevertheless, very little has been done to understand whether these proteins can be used as therapeutic targets against cancers. We present data showing for the first time that pharmacologic stimulation of specific K+ channels with small molecules strongly reduced tumor growth and metastatic spread in different animal model of cancer biology including Drosophila and mice without discernible side effects. For example, use of two chemically distinct Kv11.1 potassium channel activators showed growth arrest in an in vivo Drosophila tumor model and strongly inhibited tumor growth in SCID mice bearing the aggressive TNBC cell line MDA-MB-231. In addition, the metastatic spread of this cancer cell line in NOD-scid-IL2Rγnull was significantly reduced in terms of organs affected and metastatic burden. Interestingly, analysis of the biochemical signaling linking activation of specific K+ channels to tumor growth inhibition revealed that pharmacological stimulation of K+ channel activated a cellular senescent program that is characterized by increased expression of the tumor suppressors (e.g. p21, p16, HMGA2), formation of heterochromatin and permanent growth arrest of cancer cells independently of their molecular subtypes (including p53 negative cancer cells, breast, skin or ovarian cancer cells). Investigating on the possible mechanism linking Kv11.1 stimulation to inhibition of metastasis revealed that Kv11.1 agonists strongly inhibit cancer cell motility by suppressing nuclear function of bβ-catenin in transcribing for Epithelial to Mesenchymal Transition (EMT) markers including vimentin, CD44, N-cadherin. Concurrently, K+ channel agonists increased cytoplasmic β-catenin protein level by repressing its degradation, increased levels of the adhesive molecule E-cadherin and promoted formation of the proteins complex bβ-catenin/E-cadherin at the surface membrane. Overall, our data strongly suggest that use of K+ channel agonists can inhibit tumor progression by activating senescence and inhibit metastasis by reversing mesenchymal into epithelial phenotype (MET). We think that these are important discoveries because they offer an opportunity to identify in K+ channels proteins that can be therapeutically targeted to eliminate tumor growth and metastasis. Citation Format: Eun-Kyoung Breuer, Clodia Osipo, Jeremiah Zartman, Claire Wells, Michael Nishimura, Walter Jones, Saverio Gentile. Exploring targeting potassium channels in cancer: A novel strategy for therapeutic intervention [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B38.