Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy

Abstract

Purpose Paclitaxel is used worldwide in the treatment of breast, lung, ovarian and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCLs) and Asian patients. Methods GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare to a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human induced pluripotent stem cells were used for functional validation of candidate genes. Results SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10−6). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphological changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05) including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphological characteristics. Conclusion We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy.

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy

“…Previously, human iPSC-derived neurons have been evaluated to screen for neurotoxic compounds [Ryan, et al 2016]. Our laboratory has used commercially available iPSC-derived cortical neurons to evaluate their potential as a model of neurotoxicity [Wheeler, et al 2015] and to functionally validate genes identified in human clinical genome wide association studies of peripheral neuropathy following treatment with paclitaxel [Wheeler, et al 2015, Komatsu, et al 2015], vincristine [Diouf, et al 2015] and docetaxel [Hertz, et al 2016]. Our work reported here extends previous studies to evaluate mechanistically distinct chemotherapeutics in iPSC-derived cortical and peripheral neurons, for effects on morphological characteristics and electrical activity.…”

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy

“…Interestingly, knockdown of VAC14 seemed to decrease cellular sensitivity to paclitaxel treatment for these morphological characteristics suggesting that this gene may play an important role in the damage to processes and branching induced by docetaxel but not paclitaxel. A similar model of human neuronal cell sensitivity that utilizes induced pluripotent cortical neurons (iCell ® Neurons) has previously been used for mechanistic validation of GWAS hits that increases risk of paclitaxel-induced neuropathy(19, 33) and vincristine-induced neuropathy(11). These human model systems have several advantages over the use of rodent cell lines such as rat pheochromocytoma cell lines, PC12 or NS1.…”

Chemotherapy-induced peripheral neuropathy: Current status and progress

“…In a similar integration method using Asian cell lines and patient cohorts, when focusing more on Asian specific genes, decreased AIPL1 was found to result in decreased sensitivity of neurons to paclitaxel. In addition, breakpoint cluster region protein (BCR) was also identified to protect the neurons from paclitaxel induced toxicity [38]. Furthermore, using the CALGB 40101 patient cohort, paclitaxel-induced peripheral neuropathy was found to be heritable.…”