Streptozotocin-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), whereas targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately, objective response rates to both treatments are limited. Because mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with streptozotocin treatment in a subset of pNETs, namely insulinomas. To evaluate the potential of mTOR inhibition in combination with streptozotocin, we selected four different inhibitors acting at various levels of the pathway (everolimus: inhibition of mTORC1; MK-2206: inhibition of AKT; BKM120: inhibition of PI3K, mTORC1, and mTORC2; and BEZ235: inhibition of mTORC1 and mTORC2). Effects on cell viability and apoptosis were assessed in insulinoma cell lines INS-1E (rat) and MIN6 (mouse) in vitro and were confirmed in vivo by using a mouse model of hepatic tumor dissemination after intrasplenic xenograft. In vitro, all four combinations display synergistic effects. These combinations lead to heterogeneous mTOR pathway inhibition, in agreement with their respective target, and increased apoptosis. In vivo, tumor growth in the liver was significantly inhibited by combining streptozotocin with everolimus (P = 0.0014), BKM120 (P = 0.0092), or BEZ235 (P = 0.008) as compared to each agent alone. These results suggest that targeting the mTOR pathway in combination with streptozotocin could be of potential benefit for insulinomas and pNET patients and thus support further clinical investigations. Mol Cancer Ther; 17(1); 60–72. ©2017 AACR.

中文翻译：

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mTOR抑制剂和链脲佐菌素的联合治疗导致胰岛素瘤细胞的体外和体内协同抗肿瘤作用

基于链脲佐菌素的化疗是推荐用于晚期胰腺神经内分泌肿瘤 (pNET) 的一线化疗，而包括 mTOR 抑制剂在内的靶向治疗可用于二线治疗。不幸的是，对这两种治疗的客观反应率都是有限的。由于 mTOR 通路激活，通常在 pNET 中观察到，已被报道为解释化学抗性的主要机制之一，我们研究了 mTOR 抑制联合链脲佐菌素治疗在 pNET 子集（即胰岛素瘤）中的潜在益处。为了评估 mTOR 抑制与链脲佐菌素组合的潜力，我们选择了四种不同的抑制剂，作用于该途径的不同水平（依维莫司：mTORC1 的抑制；MK-2206：AKT 的抑制；BKM120：PI3K、mTORC1 和 mTORC2 的抑制；和 BEZ235：mTORC1 和 mTORC2 的抑制）。在体外评估胰岛素瘤细胞系 INS-1E（大鼠）和 MIN6（小鼠）对细胞活力和细胞凋亡的影响，并通过使用脾内异种移植后肝脏肿瘤扩散的小鼠模型在体内证实。在体外，所有四种组合都显示出协同效应。这些组合导致异质 mTOR 通路抑制，与它们各自的目标一致，并增加细胞凋亡。在体内，与单独使用每种药物相比，链脲佐菌素与依维莫司 (P = 0.0014)、BKM120 (P = 0.0092) 或 BEZ235 (P = 0.008) 联合使用可显着抑制肝脏中的肿瘤生长。这些结果表明，靶向 mTOR 通路与链脲佐菌素联合可能对胰岛素瘤和 pNET 患者具有潜在益处，从而支持进一步的临床研究。摩尔癌症治疗; 17(1); 60-72。©2017 AACR。