EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS

Claire E Le Pichon; Sara L Dominguez; Hilda Solanoy; Hai Ngu; Nicholas Lewin-Koh; Mark Chen; Jeffrey Eastham-Anderson; Ryan Watts; Kimberly Scearce-Levie

doi:10.1371/journal.pone.0062342

EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS

PLoS One. 2013 Apr 26;8(4):e62342. doi: 10.1371/journal.pone.0062342. Print 2013.

Authors

Claire E Le Pichon¹, Sara L Dominguez, Hilda Solanoy, Hai Ngu, Nicholas Lewin-Koh, Mark Chen, Jeffrey Eastham-Anderson, Ryan Watts, Kimberly Scearce-Levie

Affiliation

¹ Department of Neuroscience, Genentech Inc, South San Francisco, California, United States of America.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / drug therapy*
Amyotrophic Lateral Sclerosis / pathology
Animals
Astrocytes / drug effects
Astrocytes / metabolism
Astrocytes / pathology
Biomarkers / metabolism
Disease Models, Animal
Disease Progression*
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Erlotinib Hydrochloride
Humans
Longevity / drug effects
Mice
Mice, Transgenic
Microglia / drug effects
Microglia / metabolism
Microglia / pathology
Motor Neurons / drug effects
Motor Neurons / metabolism
Motor Neurons / pathology
Neuromuscular Junction / drug effects
Neuromuscular Junction / metabolism
Neuromuscular Junction / pathology
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Quinazolines / pharmacology
Quinazolines / therapeutic use*
Spinal Cord / drug effects
Spinal Cord / metabolism
Spinal Cord / pathology
Staining and Labeling
Superoxide Dismutase / genetics*
Superoxide Dismutase / metabolism
Superoxide Dismutase-1
Survival Analysis
Synapses / drug effects
Synapses / metabolism
Synapses / pathology
Time Factors

Substances

Biomarkers
Protein Kinase Inhibitors
Quinazolines
SOD1 protein, human
Erlotinib Hydrochloride
Sod1 protein, mouse
Superoxide Dismutase
Superoxide Dismutase-1
ErbB Receptors

Grants and funding

Genentech, Inc. funded this research. The study was funded by Genentech, Inc. through the employment (at the time of the study) of the authors. These authors contributed to all aspects of the study. The funders were involved in study design, data collection and analysis, decision to publish, and preparation of the manuscript.