Lipid-dependent regulation of Kv10.1 in cancer: implications of membrane remodeling for channel function and pharmacology

Vollständiger Abstract

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The voltage-gated potassium channel Kv10.1 (Eag1), which is abnormally overexpressed across a wide range of tumor types, is a promising therapeutic target for cancer treatment. However, the clinical development of Kv10.1 inhibitors is currently constrained by severe off-target cardiotoxicity resulting from unintended inhibition of the structurally homologous Kv11.1 (hERG) channel. In this review, we examined cancer-associated membrane lipid remodelling and its implications for the lipid-dependent regulation of both channels. Emerging evidence suggests that membrane lipids play a critical role in regulating voltage-gated potassium channels and that, despite their substantial structural similarity, Kv10.1 and Kv11.1 are modulated by distinct lipid-dependent mechanisms. In particular, we highlighted their differential responses to key membrane constituents, including phosphatidylinositol 4,5-bisphosphate (PIP2), cholesterol, and polyunsaturated fatty acids (PUFAs). These observations suggest that the surrounding membrane environment may represent an additional and largely underexplored factor influencing channel function. We further discuss how disease-associated lipid remodeling in cancer may contribute to altered Kv10.1 activity and highlight the possibility that such changes could influence pharmacological responses. Although the underlying mechanisms remain incompletely understood, this perspective points to an underexplored dimension in potassium channel biology that may inform future therapeutic strategies.