Genomewide Meta‐Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent‐Induced Sensory Peripheral Neuropathy

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.

Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

“…In support of these ongoing clinical evaluations, a recent pharmacogenomic study revealed that patients with CINP have single nucleotide polymorphisms (SNPs) in a genomic region that regulates S1PR1 gene expression. These findings on genetic variations validate pharmacological studies and could explain patient susceptibility and drive mechanisms underlying CINP development [120]. Validation of the next generation of S1PR modulators requires preclinical and clinical trials (see Outstanding Questions).…”

“…Functional and competitive S1PR1 antagonists block morphine-induced hyperalgesia, tolerance, and dependence 2020 [83] Activation of S1PR2 following systemic administration of the selective S1PR2 agonist CYM-5478 attenuates cisplatin-induced neuropathic pain in rats 2020 [34] Patients with CINP have single nucleotide polymorphisms (SNPs) in a genomic region that regulate S1PR1 gene expression. These genetic variations validate pharmacological studies and could explain patient susceptibility to CINP development 2020 [120]…”

Mechanistic insights into the pathogenesis of microtubule‐targeting agent‐induced peripheral neuropathy from pharmacogenetic and functional studies

“…A recent GWAS meta‐analysis of peripheral neuropathy following treatment of breast cancer patients with paclitaxel, nab‐paclitaxel or ixabepilone identified SNPs in the enhancer regions of S1PR1 encoding the G‐protein coupled receptor sphingosine‐1‐phosphate receptor 1 (S1PR 1 ) which were associated with an increased risk of developing CIPN 63 . In vitro validation studies utilizing FTY‐720 (fingolimod), a functional antagonist of S1P receptors, in combination with paclitaxel in an induced pluripotent stem cell (iPSC)‐derived sensory neuron model, demonstrated that S1PR1 inhibition confers neuronal protection against paclitaxel toxicity.…”

Genomewide Association Studies in Pharmacogenomics

“…The most studied individual cancer drugs are methotrexate and paclitaxel, with six studies each. Six independent studies have investigated PGx of paclitaxel response; four of which studied the genomics of paclitaxel‐induced peripheral neuropathy and have implicated the gene S1PR1 in peripheral neuropathy risk 21 . Other frequently studied drugs are cisplatin and other platinum compounds (13 studies), and anthracyclines (5 studies).…”