Lenvatinib and everolimus synergistically inhibit neuroendocrine neoplasms by upregulating ITGB4 expression

There are currently few treatment options available for advanced neuroendocrine neoplasms (NENs). When treating metastatic renal cancer, the combination of lenvatinib with everolimus has shown noticeably greater success than monotherapy. Clarifying the synergistic effects of lenvatinib and everolimus on NENs and investigating the underlying processes were the goals of this study. Lenvatinib and everolimus were tested for their synergistic inhibitory effects on NEN cells in vitro using CCK-8, colony formation, wound healing, flow cytometry, and tube formation. In vivo evaluation of the combined inhibitory effects was conducted using a xenograft mouse model. Western blot analysis was used to look into the main regulatory molecules implicated in this synergy, and clinical case studies were used to quantify the clinical benefits. The combination of lenvatinib and everolimus showed a synergistic anti-tumor impact in vivo and suppressed cell proliferation, colony formation, cell migration, angiogenesis, and promoted apoptosis in vitro. Notably, in patients with advanced NENs who developed resistance after many lines of therapy (>2nd line), this combination successfully postponed the advancement of their disease. Mechanistically, both medications increased the expression of ITGB4 and inhibited 4EBP1 phosphorylation; their combined inhibitory effects on NENs were lessened when ITGB4 was knocked down. These findings indicate that lenvatinib and everolimus act synergistically to inhibit NEN proliferation and migration and to induce apoptosis in vitro, with robust synergistic activity also evident in vivo. This synergy appears to be mediated, at least in part, through the upregulation of ITGB4.