Machine learning and biological validation identify sphingolipids as key mediators of paclitaxel-induced neuropathy in cancer patients

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy.High resolution mass spectrometry lipidomics was applied to quantify d = 255 different lipid mediators in the blood of n = 31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy.Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy.Present findings suggest an important role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, provides a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects.