--- - |2- Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Based on transcriptional profiles of motor cortex samples, in a previous work, we were able to classify two subgroups of sporadic ALS (SALS) patients, named SALS1 and SALS2. A further meta‐analysis study has revealed sixteen drug targets commonly deregulated in SALS2 and superoxide dismutase 1 (SOD1) G93A mice. The identified candidate drug targets included pituitary adenylate cyclase‐activating polypeptide (PACAP), epidermal growth factor receptor (EGFR) and matrix metallopeptidase‐2 (MMP‐2). By using a motor neuron‐like hybrid cell line (NSC‐34) expressing human SOD1 G93A as an in vitro model of ALS, here we investigated the functional correlation among these three genes. Our results have shown that PACAP increases cell viability following serum deprivation. This effect is induced through EGFR transactivation mediated by protein kinase A stimulation. Furthermore, EGFR phosphorylation activates mitogen‐activated protein kinases/extracellular signal‐regulated kinases 1 and 2 survival signaling pathway and increases MMP‐2 expression, significantly reduced by serum starvation. These results suggest that a deeper characterization of mechanisms involved in PACAP/EGFR/MMP‐2 axis activation in G93A SOD1 mutated neurons may allow identifying new targets for ALS therapy. - Journal of Cellular Physiology, EarlyView.