title: When will resistance be futile?
abstract: Cancer cells rapidly evolve a multitude of defense mechanisms to evade the effects of the oncologist's drug arsenal. Unfortunately, clinical strategies to overcome these lag far behind. This mismatch likely underlies our inability to implement new durable treatment strategies. Here, a new form of multidrug resistance, inducible drug glucuronidation, is discussed. This form was discovered while developing means to target a specific oncogene, the eukaryotic translation initiation factor 4E (eIF4E), with its inhibitor ribavirin. In two clinical studies, ribavirin treatment led to substantial clinical responses, but all responding patients eventually relapsed. In most cases, this was due to the overexpression of the sonic hedgehog transcription factor Gli1, which elevated the UDP glucuronsyltransferase UGT1A enzymes. UGT1As add glucuronic acid to many drugs. Indeed, these cells are resistant to not only ribavirin, but also Ara-C, and likely other drugs. Inhibition of Gli1 reduced UGT1As, eliminated drug glucuronides, and renewed sensitivity to ribavirin and Ara-C. These studies highlight that cancer cells and their resistant counterparts metabolize drugs differently from each other as well as from normal cells. Likely, these inducible modifications go beyond glucuronidation. Understanding the extent of inducible drug modifications and the pathways that drive expression of the corresponding enzymatic machinery will better position us to finally make resistance futile.
authors.affiliation: Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada. katherine.borden@umontreal.ca.
authors.forename: Katherine L B
authors.initials: KL
authors.lastname: Borden
mesh_terms: D019008:Drug Resistance, Neoplasm; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D020723:Glucuronic Acid / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012254:Ribavirin / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1; D000099148:UGT1A1 Enzyme
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase; D012254:Ribavirin; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000099148:UGT1A1 Enzyme; C400551:GLI1 protein, human