Gastric cancer (GC) is a global health issue that lacks effective treatment options. Afatinib is a tyrosine kinase inhibitor (TKI) that has shown promising results in the treatment of GC. However, resistance to afatinib is inevitable and hampers its clinical application. To date, there is limited knowledge regarding the mechanisms underlying the resistance of GC cells to afatinib. This study aimed to identify novel factors that may contribute to the resistance of GC cells to afatinib. We found that upregulation of calmodulin 2 (CALM2), a member of the CALM family, confers resistance to afatinib in GC cells. Knockdown of CALM2 can overcome the resistance to afatinib by promoting mitochondrial apoptosis in a caspase-dependent manner. Mechanistically, it was found that the downregulation of CALM2 led to the upregulation of the FoxO3a/Puma axis. Inhibition of either FoxO3a or Puma abrogated the effects of CALM2 downregulation in GC cells. In addition, we revealed that CALM2 knockdown inhibited Akt signaling, which is responsible for blocking the FoxO3a/Puma axis. Altogether, our results indicated that CALM2 could be considered a potential target to overcome the resistance of GC cells to afatinib.
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