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Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral
Katherina C Chua1,2, Chenling Xiong2, Carol Ho2
1Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, California, USA.
Abstract:
Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1 ; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254-0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334-1.053); PMETA = 3.62 × 10-7 ) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in induced pluripotent stem cell-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.
Insights
Genetic variations near S1PR1 increase risk for chemotherapy-induced peripheral neuropathy (PN). Targeting S1PR1 may prevent or treat this common side effect of microtubule targeting agents (MTAs).
Area of Science:
- Pharmacogenomics
- Neuroscience
- Oncology
Background:
- Microtubule targeting agents (MTAs) are vital anticancer drugs but cause dose-limiting sensory peripheral neuropathy (PN).
- Identifying genetic factors influencing PN susceptibility is crucial for optimizing cancer therapy and patient outcomes.
Purpose of the Study:
- To identify genetic variations associated with patient susceptibility to MTA-induced PN.
- To elucidate the underlying mechanisms driving the development of MTA-induced PN.
Main Methods:
- Meta-analysis of genomewide association studies (GWAS) from two clinical cohorts (CALGB 40502 and CALGB 40101).
- Cox regression modeling to assess the risk of grade 2 or higher PN based on cumulative MTA dose.
- In silico functional analysis and in vitro studies using human sensory neurons.
Main Results:
- Novel single nucleotide polymorphisms (SNPs) in an enhancer region downstream of S1PR1 were significantly associated with increased risk of MTA-induced PN (PMETA = 3.62 × 10-7).
- Functional analysis indicated regulatory elements and enhancer activity for S1PR1 in this region.
- Inhibition of S1PR1 provided partial protection against paclitaxel-induced neurite damage in human sensory neurons.
Conclusions:
- Pharmacogenetic findings highlight S1PR1 as a key player in MTA-induced PN.
- Targeting S1PR1 presents a potential therapeutic strategy for preventing or treating chemotherapy-induced neuropathy.
