SK3 gene polymorphism is associated with taxane neurotoxicity and cell calcium homeostasis

Abstract

Purpose: Taxane-induced peripheral neuropathy is a common side effect induced by anticancer agents, and no drug capable of preventing its occurrence or ameliorating its longterm course has been identified. The physiology of taxane neuropathy is not clear, and diverse mechanisms have been suggested, with ion channels regulating Ca2+ homeostasis appearing good candidates. The calcium-activated potassium channel SK3 is encoded by the KCNN3 gene, which is characterized by a length polymorphism due to variable number of CAG repeats. Experimental Design: To study the influence of the polymorphism of CAG motif repeat of KCNN3 on the development of taxane-induced neuropathy, we evaluated 176 patients treated with taxanes for breast cancer. In parallel, we measured Ca2+ entry using Fura2-AM dye in HEK cells expressing short versus long CAG alleles of KCNN3. Results: In the current study, we report that in the presence of docetaxel, Ca2+ entry was significantly increased in cells expressing short versus long CAG alleles of SK3 and that a SK3- lipid blocker inhibits this effect. We found that patients carrying a short KCNN3 allele exhibited significantly increased incidence of taxane neuropathy compared with those carrying longer alleles. Conclusions: The clinical implication of these findings is that KCNN3 polymorphism may increase patient susceptibility to taxane neurotoxicity and that the use of SK3 blockers during taxanes' administration may represent an interesting approach for the prevention of this neurotoxicity.