Clinical Cancer Research
Discovery of single nucleotide polymorphisms (SNPs) that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.
A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.
498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. A SNP in VAC14 (rs875858) surpassed genome-wide significance (p=2.12×10-8 adjusted p=5.88×10-7). siRNA knockdown of VAC14 in stem cell derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (p=0.0015) and branches (p<0.0001). Prior to docetaxel treatment VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (p=0.001).
VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization.
Hertz, Daniel L.; Owzar, Kouros; Lessans, Sherrie; Wing, Claudia; Jiang, Chen; Kelly, William Kevin; Patel, Jai; Halabi, Susan; Furukawa, Yoichi; Wheeler, Heather E.; Sibley, Alexander B.; Lassiter, Cameron; Weisman, Lois; Watson, Dorothy; Krens, Stefanie D.; Mulkey, Flora; Renn, Cynthia L.; Small, Eric J.; Febbo, Phillip G.; Shterev, Ivo; Kroetz, Deanna L.; Friedman, Paula N.; Mahoney, John F.; Carducci, Michael A.; Kelley, Michael J.; Nakamura, Yusuke; Kubo, Michiaki; Dorsey, Susan G.; Dolan, M. Eileen; Morris, Michael J.; and McLeod, Howard L.. Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism That Increases Risk of Docetaxel-Induced Neuropathy. Clinical Cancer Research, 22, 19: 4890-4900, 2016. Retrieved from Loyola eCommons, Biology: Faculty Publications and Other Works, http://dx.doi.org/10.1158/1078-0432.CCR-15-2823
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© American Association for Cancer Research 2016