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Clinical Trial
. 2016 Oct 1;22(19):4890-4900.
doi: 10.1158/1078-0432.CCR-15-2823. Epub 2016 May 3.

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

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Free PMC article
Clinical Trial

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

Daniel L Hertz et al. Clin Cancer Res. .
Free PMC article

Abstract

Purpose: Discovery of 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.

Experimental design: 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.

Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An 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).

Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890-900. ©2016 AACR.

Conflict of interest statement

The authors declare the following relevant conflicts of interest.

Figures

Figure 1
Figure 1. Genome-wide association results
Manhattan plot displaying the unadjusted p-value for the association of cumulative docetaxel dose at grade 3+ sensory neuropathy for all SNPs that passed quality control (n=498,022). One SNP (rs875858) surpassed the Bonferonni-corrected significance threshold of 1.0×10-7.
Figure 2
Figure 2. Incidence of Neuropathy by Genotype for Highly Associated SNPs
Cumulative incidence curve of docetaxel dose at grade 3+ neuropathy occurrence stratified by genotype for the top three hits: A) a VAC14 intronic SNP (rs875858), B) an intergenic SNP (rs11017056), and C) an ATP8A2 intronic SNP (rs1326116). In each case, carrying the variant allele increased neuropathy risk compared to wild-type patients, though there were too few patients who were homozygous for the rare VAC14 variant (n=3) to draw meaningful conclusions in this group.
Figure 2
Figure 2. Incidence of Neuropathy by Genotype for Highly Associated SNPs
Cumulative incidence curve of docetaxel dose at grade 3+ neuropathy occurrence stratified by genotype for the top three hits: A) a VAC14 intronic SNP (rs875858), B) an intergenic SNP (rs11017056), and C) an ATP8A2 intronic SNP (rs1326116). In each case, carrying the variant allele increased neuropathy risk compared to wild-type patients, though there were too few patients who were homozygous for the rare VAC14 variant (n=3) to draw meaningful conclusions in this group.
Figure 2
Figure 2. Incidence of Neuropathy by Genotype for Highly Associated SNPs
Cumulative incidence curve of docetaxel dose at grade 3+ neuropathy occurrence stratified by genotype for the top three hits: A) a VAC14 intronic SNP (rs875858), B) an intergenic SNP (rs11017056), and C) an ATP8A2 intronic SNP (rs1326116). In each case, carrying the variant allele increased neuropathy risk compared to wild-type patients, though there were too few patients who were homozygous for the rare VAC14 variant (n=3) to draw meaningful conclusions in this group.
Figure 3
Figure 3. VAC14 Knockdown increases neuronal cell sensitivity to docetaxel but decreases sensitivity to paclitaxel
A) Peripheral neuron (Peri.4U) experimental scheme illustrating timing of treatment and imaging. B) Relative VAC14 expression at 24, 48 and 72 hours post-transfection with siVAC14 compared to non-targeting control (NTC) produced a steady decline of VAC14 expression over time. The neurite outgrowth changes after 24 hours docetaxel (48 hours knockdown) showed no significance as measured by C) total outgrowth but did result in greater sensitivity to docetaxel in D) relative number of processes and E) relative number of branches. Alternatively, VAC14 knockdown decreased peripheral neuronal cell sensitivity to paclitaxel, 3F-3H. Open circle represent data from VAC14 siRNA and closed circle from NTC siRNA. Neurite parameters measured with MetaXPress® software were averaged from 3 independent experiments. Error bars represent the standard error of the mean from three independent transfection experiments. NTC = non-targeting control, UT= untransfected control.
Figure 4
Figure 4. Docetaxel Treatment Increases Nociceptive Sensitivity in VAC14 Heterozygous and Wild-type Mice
The withdrawal threshold is defined as the lightest fiber weight that caused each mouse to withdraw their hind paw at least three times out of five. Each mouse has a withdrawal threshold at each time-point in the study. The mean withdrawal threshold is the average of 12-14 mice (6-7 for each gender) for each treatment condition (VAC14 genotype and docetaxel treatment). Docetaxel- treated mice of either genotype had greater hindpaw withdrawal sensitivity following the end of treatment at day 8 compared to the untreated control mice (p<0.0001). There was no significant difference in the docetaxel-induced increase in withdrawal sensitivity comparing VAC14 heterozygous and wild-type mice (p=0.18).

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