Integrated Systems Pharmacology Analysis of Clinical Drug-Induced Peripheral Neuropathy

A systems pharmacology approach was undertaken to define and identify the proteins/genes significantly associated with clinical incidence and severity of drug‐induced peripheral neuropathy (DIPN). Pharmacological networks of 234 DIPN drugs, their known targets (both intended and unintended), and the intermediator proteins/genes interacting with these drugs via their known targets were examined. A permutation test identified 230 DIPN‐associated intermediators that were enriched with apoptosis and stress response genes. Neuropathy incidence and severity were curated from drug labels and literature and were used to build a predictive model of DIPN using a regression tree algorithm, based on the drug targets and their intermediators. DIPN drugs whose targets interacted with both v‐myc avian myelocytomatosis viral oncogene homolog (MYC) and proliferating cell nuclear antigen‐associated factor (PAF15) were associated with a neuropathy incidence of 38.1%, whereas drugs interacting only with MYC had an incidence of 2.9%. These results warrant further investigation in order to develop a predictive tool for the DIPN potential of a new drug.

[1]  H. Goldschmidt,et al.  Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. , 2010, The Lancet. Oncology.

[2]  J. Hallas,et al.  Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? , 2001, European Journal of Clinical Pharmacology.

[3]  J. Busserolles,et al.  Emerging Trends in Understanding Chemotherapy-Induced Peripheral Neuropathy , 2013, Current Pain and Headache Reports.

[4]  Wei-Yin Loh,et al.  Variable Selection for Classification and Regression in Large p, Small n Problems , 2012 .

[5]  Allan Kuchinsky,et al.  GLay: community structure analysis of biological networks , 2010, Bioinform..

[6]  Yang Song,et al.  Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery , 2011, Nucleic Acids Res..

[7]  Jennifer M. Rust,et al.  The BioGRID Interaction Database , 2011 .

[8]  R. Rosenfeld.  Patients , 2012, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[9]  M. Dolan,et al.  Regulatory Polymorphisms in β-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy , 2012, Clinical Cancer Research.

[10]  S. Feinstein,et al.  Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. , 2013, Neurotoxicology.

[11]  A. Ocean,et al.  Peripheral neuropathy with microtubule-targeting agents: occurrence and management approach. , 2011, Clinical breast cancer.

[12]  David S. Wishart,et al.  DrugBank 3.0: a comprehensive resource for ‘Omics’ research on drugs , 2010, Nucleic Acids Res..

[13]  P. Bork,et al.  A side effect resource to capture phenotypic effects of drugs , 2010, Molecular systems biology.

[14]  J. Paice,et al.  Clinical challenges: chemotherapy-induced peripheral neuropathy. , 2009, Seminars in oncology nursing.

[15]  Yusuke Nakamura,et al.  A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101 , 2012, Clinical Cancer Research.

[16]  N. Staff,et al.  Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons. , 2013, Neurotoxicology.

[17]  Christie S. Chang,et al.  The BioGRID interaction database: 2013 update , 2012, Nucleic Acids Res..

[18]  Joon-Oh Park,et al.  Polymorphic markers associated with severe oxaliplatin‐induced, chronic peripheral neuropathy in colon cancer patients , 2012, Cancer.

[19]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[20]  Leslie Wilson,et al.  Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. , 2010, Biochemistry.

[21]  豊 木村,et al.  胃癌手術におけるCommon Terminology Criteria for Adverse Events v3.0を利用した合併症の評価 , 2009 .

[22]  Cancer Therapy Evaluation Program.  Common Terminology Criteria for Adverse Events v3.0 (CTCAE) , 2003 .

[23]  P. Wen,et al.  Management of treatment-emergent peripheral neuropathy in multiple myeloma , 2012, Leukemia.

[24]  W. Loh,et al.  REGRESSION TREES WITH UNBIASED VARIABLE SELECTION AND INTERACTION DETECTION , 2002 .

[25]  A. González-Neira,et al.  Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy , 2013, Journal of Medical Genetics.

[26]  Martin G. Brodwin.  Book , 2010, Journal of Applied Rehabilitation Counseling.

[27]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[28]  Ivo D. Shterev,et al.  Integration of Cell Line and Clinical Trial Genome-Wide Analyses Supports a Polygenic Architecture of Paclitaxel-Induced Sensory Peripheral Neuropathy , 2012, Clinical Cancer Research.

[29]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[30]  T. Fojo,et al.  Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: A possible mechanism contributing to peripheral neuropathy and cellular toxicity following proteasome inhibition , 2008, Cell cycle.