Falletta Simona, Partelli Stefano, Rubini Corrado, Nann Dominik, Doria Andrea, Marinoni Ilaria, Polenta Vanessa, Di Pasquale Carmelina, Degli Uberti Ettore, Perren Aurel, Falconi Massimo, Zatelli Maria Chiara
Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.
Pancreatic Surgery UnitPancreas Translational and Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.
Endocr Relat Cancer. 2016 Nov;23(11):883-891. doi: 10.1530/ERC-16-0329. Epub 2016 Oct 3.
Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus.
胰腺神经内分泌肿瘤（P-NET）的药物治疗可采用依维莫司。然而，治疗反应的程度无法预测。本研究旨在确定P-NET中对依维莫司反应的可能预测标志物。我们发现依维莫司降低了6例P-NET原代培养物（P-NET-R）的细胞活力并诱导凋亡，在这些培养物中依维莫司阻断了IGF1的增殖和抗凋亡作用。相反，14例P-NET原代培养物（P-NET-NR）对依维莫司和IGF1耐药，提示PI3K/AKT/mTOR通路参与了耐药机制。体外对依维莫司的反应与活跃的AKT/mTOR通路相关，且似乎与更高的临床侵袭性有关。此外，一名在体外对依维莫司敏感的患者在体内也对该药物敏感，且在组织水平上p-AKT免疫组化（IHC）呈阳性。同样，一名术后对依维莫司治疗耐药的患者在体外对该药物不敏感，且p-AKT IHC染色为阴性。因此，目前的数据证实P-NET原代培养物可被视为测试药物治疗疗效的模型，且p-AKT的IHC特征可能有助于识别可从依维莫司治疗中获益的人类P-NET。这些数据鼓励开展一项前瞻性多中心研究，纳入接受依维莫司治疗的不同组P-NET患者。
