CPI-613 Suppresses Pancreatic Cancer Stem-Like Cells by Targeting the SEMA3A/NRP1 Pathway

Abstract

Abstract Pancreatic cancer is known for its recurrence and chemotherapy resistance, partly attributed to cancer stem cells (CSCs). Targeting CSCs could improve the efficacy of standard cytotoxic therapies and potentially prevent or delay cancer recurrence. The increased reliance on the modulation of metabolic pathways in CSCs offers a potential therapeutic opportunity. In this study, we investigated the effects of CPI-613 (Dedvimistat), a metabolic inhibitor that targets the tricarboxylic acid cycle on pancreatic cancer cells. We demonstrate that treatment with CPI-613 significantly reduced the capacity to form CSCs, furthermore, CPI-613 showed decreased tumorigenicity in vivo. To gain further insights into the molecular mechanisms underlying the effects of CPI-613, RNA-Seq analysis was performed. CPI-613 impeded the unintended enrichment of CSC through target SEMA3A (Semaphorin 3A) and its receptor NRP1 (Neuropilin 1). Knockdown of SEMA3A significantly inhibited the proliferation of CD44 + frequency and increased their sensitivity to gemcitabine. Moreover, treatment with exogenous SEMA3A counteracted the inhibitory effect of CPI-613 on CSC proliferation and promoted resistance to gemcitabine. Our findings suggest that CPI-613 selectively targets pancreatic CSCs through the SEMA3A/NRP1 pathway. CPI-613 has the potential to overcome chemoresistance and prevent cancer recurrence by targeting CSCs.