mTORC1 抑制剂依维莫司是少数获批治疗局部晚期和转移性神经内分泌肿瘤 (NET) 的疗法之一。然而，在疾病最初稳定后，大多数患者在一年内出现耐药性。我们的目的是通过在依维莫司耐药的原位胰腺神经内分泌癌异种移植小鼠模型中使用 PI3Kα 抑制剂 alpelisib 进行额外治疗来克服对依维莫司的耐药性。雌性 SCID 小鼠接受依维莫司敏感 (BON1KDMSO) 或依维莫司耐药 (BON1RR2) NET 细胞的腹腔镜胰腺移植。两组均进一步分为 4 个治疗组：安慰剂、依维莫司、alpelisib 和依维莫司 alpelisib（组合）。口服治疗从肿瘤体积约 140 mm3 开始，一直持续到 1900 - 2000 mm3，通过每周 MRI 进行验证。通过 68Ga-DOTATOC- 和 18F-FDG PET/CT 分析生长抑素受体表达和肿瘤活力。证实了 BON1RR2 肿瘤的依维莫司耐药性。在依维莫司敏感组中，与安慰剂相比，单独的依维莫司、单独的alpelisib和联合治疗显着延长了生存期，而在BON1RR2组中，单独的联合治疗与安慰剂相比显着延长了生存期，但单独的依维莫司和alpelisib都没有。与安慰剂治疗的依维莫司耐药肿瘤（60 天）相比，安慰剂治疗的依维莫司敏感肿瘤生长更快（中位生存期 45 天）。在依维莫司敏感组中，联合治疗的小鼠表现出最长的中位生存期（52 天）。在所有组中，依维莫司耐药联合治疗组存活时间最长（69 天）。依维莫司和阿培利西布的联合治疗似乎有望克服神经内分泌肿瘤中的依维莫司耐药性，应在临床试验中进一步检验。

The mTORC1 inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). However, after initial disease stabilisation, most patients develop resistance within one year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3Kalpha inhibitor alpelisib in an everolimus-resistant orthotopic pancreatic neuroendocrine carcinoma xenograft mouse model. Female SCID mice underwent laparoscopic pancreatic transplantation of everolimus-sensitive (BON1KDMSO) or everolimus-resistant (BON1RR2) NET cells. Both groups were further divided into 4 treatment groups: placebo, everolimus, alpelisib and everolimus + alpelisib (combination). Oral treatment was started at a tumour volume of approximately 140 mm3 and continued until 1900 - 2000 mm3, validated by weekly MRI. Somatostatin receptor expression and tumour viability were analysed by 68Ga-DOTATOC- and 18F-FDG PET/CT. Everolimus resistance of the BON1RR2 tumours was confirmed. In the everolimus-sensitive group, everolimus alone, alpelisib alone and combination treatment significantly prolonged survival, compared to placebo, while in the BON1RR2 group, only combination treatment significantly prolonged survival compared to placebo, but neither everolimus nor alpelisib alone. Placebo-treated everolimus-sensitive tumours grew more rapidly (median survival 45 d), compared to placebo-treated everolimus-resistant tumours (60 d). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 d). Of all groups, the everolimus-resistant combination-treated group survived longest (69 d). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.