title: Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs.
abstract: Acquired resistance to cancer drug therapies almost always occurs in advanced-stage patients even following a significant response to treatment. In addition to mutational mechanisms, various non-mutational resistance mechanisms have now been recognized. We previously described a chromatin-mediated subpopulation of reversibly drug-tolerant persisters that is dynamically maintained within a wide variety of tumour cell populations. Here we explore a potential role for microRNAs in such transient drug tolerance. Functional screening of 879 human microRNAs reveals miR-371-3p as a potent suppressor of drug tolerance. We identify PRDX6 (peroxiredoxin 6) as a key target of miR-371-3p in establishing drug tolerance by regulating PLA2/PKCα activity and reactive oxygen species. PRDX6 expression is associated with poor prognosis in cancers of multiple tissue origins. These findings implicate miR-371-3p as a suppressor of PRDX6 and suggest that co-targeting of peroxiredoxin 6 or modulating miR-371-3p expression together with targeted cancer therapies may delay or prevent acquired drug resistance.
authors.affiliation: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Nisebita
authors.initials: N
authors.lastname: Sahu
authors.affiliation: Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.affiliation: Department of Translational Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Darlene Dela
authors.initials: DD
authors.lastname: Cruz
authors.affiliation: Department of Translational Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Richard
authors.identifier: 0000-0002-5890-4374
authors.initials: R
authors.lastname: Bourgon
authors.affiliation: Department of Cancer Targets, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Classon
authors.affiliation: Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D054465:Peroxiredoxin VI / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C554834:MIRN371 microRNA, human; D035683:MicroRNAs; D054465:Peroxiredoxin VI; D051571:Protein Kinase C-alpha; D054467:Phospholipases A2; D054799:Phospholipase C beta