SK3 Gene Polymorphism Is Associated with Taxane Neurotoxicity and Cell Calcium Homeostasis.

Abstract

<b>Purpose:</b> Taxane-induced peripheral neuropathy is a common side effect induced by anticancer agents, and no drug capable of preventing its occurrence or ameliorating its long-term 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 <i>KCNN3</i> gene, which is characterized by a length polymorphism due to variable number of CAG repeats.<b>Experimental Design:</b> To study the influence of the polymorphism of CAG motif repeat of <i>KCNN3</i> 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 <i>KCNN3</i> <b>Results:</b> 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 <i>KCNN3</i> allele exhibited significantly increased incidence of taxane neuropathy compared with those carrying longer alleles.<b>Conclusions:</b> The clinical implication of these findings is that <i>KCNN3</i> 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. <i>Clin Cancer Res; 24(21); 5313-20. ©2018 AACR</i>.