The Molecular and Clinical Impact of Atorvastatin Exposure on Paclitaxel Neurotoxicity in Sensory Neurons and Cancer Patients

Recent evidence suggests that atorvastatin exacerbates paclitaxel neurotoxicity via P-glycoprotein inhibition. We used a translational approach to investigate if atorvastatin or simvastatin exacerbates (i) paclitaxel neurotoxicity in human sensory neurons and (ii) paclitaxel-induced peripheral neuropathy (PIPN) in cancer patients. Paclitaxel neurotoxicity was assessed by quantifying neuronal networks of human induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) with and without atorvastatin or simvastatin exposure. We estimated the odds ratio (OR) of early paclitaxel discontinuation due to PIPN in a nationwide cohort of paclitaxel-treated women (2014-2018), comparing atorvastatin users to simvastatin users and nonusers of statins. Only the highest concentration of atorvastatin (100 nM) significantly exacerbated paclitaxel neurotoxicity in iPSC-SNs (p < 0.05). Among 576 paclitaxel-treated women, atorvastatin use was not significantly associated with early paclitaxel discontinuation due to PIPN, with adjusted ORs of 0.80 [95% confidence interval (CI) 0.34-1.88] compared with simvastatin, and 1.24 [95% CI 0.44-3.53] compared with nonuse. Supplementary analyses showed varying but statistically nonsignificant results. Our in vitro findings suggest that atorvastatin, not simvastatin, significantly worsens paclitaxel neurotoxicity. However, no link was found between atorvastatin use and early paclitaxel discontinuation due to PIPN. Larger, well-designed studies are required to clarify the discrepancy between in vitro and clinical data and the inconsistencies with previous clinical evidence.