Enhanced antitumor efficacy of sorafenib and everolimus combination in pancreatic neuroendocrine neoplasms through mTOR inhibition.

Abstract

Background: Pancreatic neuroendocrine neoplasms (pNENs) represent a rare group of highly heterogeneous tumors derived from pancreatic epithelial cells exhibiting neuroendocrine differentiation properties. Everolimus, an oral inhibitor of mTOR, is the most promising drug for patients with unresectable, metastatic disease, particularly in progressive well-differentiated pNENs. Sorafenib is utilized in the treatment of hepatocellular carcinoma (HCC), renal cell carcinoma, and differentiated thyroid cancer. Furthermore, it plays an indispensable role in the management of multisystem malignancies. This study aims to investigate the effects and mechanisms of sorafenib, as well as its potential for combination use with everolimus in pNENs.

Methods: QGP-1and BON-1cells were collected from routine in vitro culture and treated with various concentrations of sorafenib, everolimus, and dual-drug combinations for 24 hours. The capacity of these medications to influence tumor activity was evaluated through the use of the Cell Counting Kit-8 (CCK-8) assay, cloning assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, transwell assay, and analysis of the xenograft tumor model. Western blot analysis was conducted to detect the level of mTOR in QGP-1 and BON-1 cells.

Results: Compared to the control group, the proliferation and migration of sorafenib-treated cells were significantly inhibited. Furthermore, as drug concentration increased, the proliferation rates of both cell types decreased. Notably, the inhibition of cell proliferation was more pronounced in the sorafenib and everolimus combination group than in the single-drug group. Western blot results indicated that the expression level of mTOR was down-regulated in the experimental group after treatment with sorafenib, everolimus, and the dual-drug combination for 24 hours, compared to the control group. In experiments involving animals, tumors in the groups treated with both high and low doses of sorafenib were smaller than those observed in the control group, and liver metastasis was suppressed in the experimental groups when compared to the control.

Conclusions: Sorafenib can inhibit the proliferation and migration of pNENs by down-regulating the mTOR pathway. The combination of sorafenib and everolimus exhibits a stronger anti-tumor effect.