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Although the deregulation of epidermal growth factor receptor ( EGFR ) is one of the most common molecular mechanisms of glioblastoma ( GBM ) pathogenesis, the efficacy of anti‐ EGFR  therapy is limited. Additionally, response to anti‐ EGFR  therapy is not solely dependent on  EGFR  expression and is more promising in patients with reduced activity of  EGFR  downstream signaling pathways. Thus, there is considerable interest in identifying the compensatory regulatory factors of the  EGFR  signaling pathway to improve the efficacy of anti‐ EGFR  therapies for  GBM . In this study, we confirmed the low efficacy of  EGFR  inhibitors in  GBM  patients by meta‐analysis. We then identified a negative correlation between connexin 43 (Cx43) expression and Akt/ ERK  activation, which was caused by the direct interactions between Akt/ ERK  and Cx43. By comparing the interactions between Akt/ ERK  and Cx43 using a series of truncated and mutated Cx43 variants, we revealed that the residues T286/A305/Q308/Y313 and S272/S273 at the carboxy terminus of Cx43 are critical for its binding with Akt and  ERK , respectively. In addition, Kaplan–Meier survival analysis using data from The Cancer Genome Atlas datasets indicated that the expression of Cx43 significantly improved the prognosis of  GBM  patients who express  EGFR . Together, our results suggested that Cx43 acts as an inhibitory regulator of the activation of growth factor receptor downstream signaling pathways, indicating the potential of Cx43 as a marker for predicting the efficacy of  EGFR  inhibitor treatments for  GBM . Targeting the interaction between the carboxy terminus of Cx43 and Akt/ ERK  could be an effective therapeutic strategy against  GBM .

Connexin 43 C‐terminus directly inhibits the hyperphosphorylation of Akt/ ERK through protein–protein interactions in glioblastoma