title: EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.
authors: Department of Neuroscience, Genentech Inc, South San Francisco, California, United States of America.
authors: Claire E
authors: CE
authors: Le Pichon
authors: Sara L
authors: SL
authors: Dominguez
authors: Hilda
authors: H
authors: Solanoy
authors: Hai
authors: H
authors: Ngu
authors: Nicholas
authors: N
authors: Lewin-Koh
authors: Mark
authors: M
authors: Chen
authors: Jeffrey
authors: J
authors: Eastham-Anderson
authors: Ryan
authors: R
authors: Watts
authors: Kimberly
authors: K
authors: Scearce-Levie
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013194:Staining and Labeling; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C000606290:SOD1 protein, human; D000069347:Erlotinib Hydrochloride; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D066246:ErbB Receptors
references: Eur J Neurosci. 2004 Oct;20(7):1745-51
references: 15379995
references: Nature. 2007 Jan 11;445(7124):168-76
references: 17151600
references: Anticancer Drugs. 2004 Jun;15(5):503-12
references: 15166626
references: Glia. 1998 Jul;23(3):249-56
references: 9633809
references: J Neurosci. 2000 Apr 1;20(7):2534-42
references: 10729333
references: Nat Biotechnol. 2008 Jan;26(1):127-32
references: 18183025
references: J Cell Biol. 2009 Dec 14;187(6):761-72
references: 19951898
references: PLoS One. 2009 Aug 03;4(8):e6489
references: 19649300
references: Neuroreport. 2004 Oct 5;15(14):2271-4
references: 15371748
references: Lab Anim (NY). 2011 Feb;40(2):53-7
references: 21252981
references: J Neurosci. 2007 Jun 13;27(24):6428-35
references: 17567803
references: J Neurochem. 2011 Jun;117(6):1066-74
references: 21517849
references: Neurobiol Dis. 2003 Aug;13(3):264-72
references: 12901841
references: J Neurosci. 2006 Jul 12;26(28):7532-40
references: 16837601
references: Muscle Nerve. 2005 Jul;32(1):43-50
references: 15880561
references: Nat Biotechnol. 2005 Mar;23(3):329-36
references: 15711537
references: Amyotroph Lateral Scler. 2008;9(1):4-15
references: 18273714
references: Nat Genet. 2010 May;42(5):392-9
references: 20348957
references: J Pharmacol Exp Ther. 1999 Nov;291(2):739-48
references: 10525095
references: Science. 1994 Jun 17;264(5166):1772-5
references: 8209258
references: Mol Cell Neurosci. 1995 Aug;6(4):349-62
references: 8846004
references: J Neurosci. 2012 May 2;32(18):6391-410
references: 22553043
references: J Histochem Cytochem. 2003 May;51(5):575-84
references: 12704205
references: Cochrane Database Syst Rev. 2001;(4):CD001447
references: 11687111
references: Science. 1995 Jul 14;269(5221):230-4
references: 7618084
references: J Neuropathol Exp Neurol. 2011 Aug;70(8):662-77
references: 21760539
references: Neuroreport. 1998 Mar 30;9(5):775-8
references: 9579663
references: J Alzheimers Dis. 2011;25(1):119-33
references: 21368377
references: J Mol Neurosci. 2009 Jun;38(2):85-93
references: 18651250