Synergistic Anti-Tumor Effects of Sulfatinib and Kaempferol on Pancreatic Neuroendocrine Tumors via CALCA-mediated PI3K/AKT/mTOR Pathway

Pancreatic neuroendocrine tumors (pNETs) represent a diverse category of neoplasms originating from pancreatic neuroendocrine cells. Although these tumors generally exhibit a relatively indolent nature, they often metastasize early in their course, significantly affecting patient outcomes. Sulfatinib (SULF) is associated with considerable toxicity and resistance challenges, leading to many patients failing to achieve long-term disease management. In contrast, Kaempferol (KMP), a naturally occurring phytochemical, has shown considerable promise in anti-tumor treatments. Our study revealed that the combination of SULF and low-dose KMP enhances the sensitivity of pNET cells to SULF. Moreover, this combination demonstrated a synergistic effect on angiogenesis inhibition, observed in both <i>in vitro</i> and <i>in vivo</i> environments. Additionally, we confirmed this synergistic anti-tumor effect using a subcutaneous tumor model of pNETs. Transcriptome sequencing identified CALCA as a key molecule in the synergistic inhibition of pNETs proliferation by SULF and KMP. In summary, our findings provide novel insights into combination therapy for pNETs while elucidating the mechanistic role of CALCA in the modulation of angiogenesis. This research establishes a foundation for the development of vascular-targeted combination therapeutic strategies for the treatment of pNETs.