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.