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Drug resistance inhibits the efficacy of doxorubicin in gastric cancer. Phosphatidylinositol 3,4,5‑trisphosphate RAC exchanger 2a (P‑REX2a) activates the phosphatidylinositol‑3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway by binding to and inactivating phosphatase and tensin homolog (PTEN), which functions as a tumor promoter in a number of types of cancer. However, there is no research concerning the association between P‑REX2a expression and drug resistance in gastric cancer. In the present study, the expression of P‑REX2a in clinical gastric cancer tissues was detected, and the mechanism of doxorubicin resistance in the gastric cancer cell line SGC7901 was investigated. Using reverse transcription‑quantitative polymerase chain reaction and western blotting, it was demonstrated that the mRNA and protein expression of P‑REX2a was increased in gastric cancer tissues. MTT assays were also used to determine proliferation, and proliferation was revealed to be reduced following transfection of P‑REX2a small interfering (si)RNA. When the cells were treated with 0.3 μM doxorubicin for 24 h, the rate of apoptosis in the siRNA‑transfected groups significantly increased and no marked changes in of PTEN and Akt expression were observed. By contrast, the activity of PTEN increased, and the expression of p‑Akt (S473) decreased in the P‑REX2a siRNA‑transfected group compared with the control. The detection of PTEN enzymatic activity in the present study was based on phosphatidylinositol‑3,4,5‑trisphosphate. Therefore, it was concluded that P‑REX2a may participate in the generation of resistance to doxorubicin in gastric cancer, and this may be associated with the upregulation of the PI3K/Akt signaling pathway via inactivation of PTEN. [ABSTRACT FROM AUTHOR]