Newcastle disease virus harboring the PTEN gene inhibits pancreatic cancer growth by inhibiting PI3K/AKT/mTOR signaling and activating apoptosis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and intractable cancer that requires more effective therapies that can improve early detection, enhance treatment efficacy, and provide better patient outcomes. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and reduced phosphatase and tensin homolog (PTEN) protein expression are key factors driving the proliferation and severity of PDAC. To address this, a recombinant Newcastle disease virus (rNDV) containing the PTEN gene (rNDV-PTEN) was created to investigate its PDAC cell-killing and tumor-suppression effects in PDAC cells transplanted into mice. PTEN expression induced by rNDV-PTEN virus infection in KRAS-mutated PDAC cells lowered phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, promoted PDAC cell death, and suppressed tumor growth. PTEN overexpression promotes apoptotic signaling pathways in both PANC-1 cells and orthotopic xenograft mice. Additionally, during virotherapy, rNDV-PTEN-injected mice exhibited a mild immune response and no abnormal responses in blood parameters such as glucose, triglyceride, and total cholesterol levels. These findings support the potential of rNDV-PTEN as a safe and effective therapy for PDAC with highly activated PI3K/AKT/mTOR signaling caused by KRAS and PTEN gene mutations. Thus, PTEN gene-containing rNDV may be a promising candidate for pancreatic cancer treatment.

Keywords

• MT: Regular Issue
• Newcastle disease virus
• pancreatic ductal adenocarcinoma
• oncolytic virus
• phosphatase and tensin homolog