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Combinatorial Treatment with Mtor Inhibitors and Streptozotocin Leads Published OnlineFirst October 19, 2017; DOI: 10.1158/1535-7163.MCT-17-0325 Small Molecule Therapeutics Molecular Cancer Therapeutics Combinatorial Treatment with mTOR Inhibitors and Streptozotocin Leads to Synergistic In Vitro and In Vivo Antitumor Effects in Insulinoma Cells Julien Bollard1,2,Celine Patte1,2, Patrick Massoma2, Isabelle Goddard2, Nicolas Gadot3, Noura Benslama2,Valerie Hervieu1,2,4,5, Carole Ferraro-Peyret2,4,5, Martine Cordier-Bussat2, Jean-Yves Scoazec6,7, Colette Roche1,2, Thomas Walter1,2,5,8, and Cecile Vercherat1,2 Abstract Streptozotocin-based chemotherapy is the first-line chemo- mTORC1 and mTORC2). Effects on cell viability and apoptosis therapy recommended for advanced pancreatic neuroendocrine were assessed in insulinoma cell lines INS-1E (rat) and MIN6 tumors (pNETs), whereas targeted therapies, including mTOR (mouse) in vitro and were confirmed in vivo by using a mouse inhibitors, are available in second-line treatment. Unfortunate- model of hepatic tumor dissemination after intrasplenic xeno- ly, objective response rates to both treatments are limited. graft. In vitro, all four combinations display synergistic effects. Because mTOR pathway activation, commonly observed in These combinations lead to heterogeneous mTOR pathway pNETs, has been reported as one of the major mechanisms inhibition, in agreement with their respective target, and accounting for chemoresistance, we investigated the potential increased apoptosis. In vivo, tumor growth in the liver was benefit of mTOR inhibition combined with streptozotocin significantly inhibited by combining streptozotocin with ever- treatment in a subset of pNETs, namely insulinomas. To eval- olimus (P ¼ 0.0014), BKM120 (P ¼ 0.0092), or BEZ235 (P ¼ uate the potential of mTOR inhibition in combination with 0.008) as compared to each agent alone. These results suggest streptozotocin, we selected four different inhibitors acting at that targeting the mTOR pathway in combination with strep- various levels of the pathway (everolimus: inhibition of tozotocin could be of potential benefit for insulinomas and mTORC1; MK-2206: inhibition of AKT; BKM120: inhibition pNET patients and thus support further clinical investigations. of PI3K, mTORC1, and mTORC2; and BEZ235: inhibition of Mol Cancer Ther; 17(1); 60–72. Ó2017 AACR. Introduction these rare and heterogeneous tumors display variable behavior in term of evolution and response to treatment. First-line treat- Therapeutic care of advanced pancreatic neuroendocrine ment of advanced pNETs is based on different prognostic factors tumors (pNETs) raises challenging clinical questions. Indeed, and two main strategies are currently described (1): (i) no che- motherapy with a watch-and-wait approach, or somatostatin analogues (SSA), for nonfunctional pNETs with low proliferative 1 Groupe des tumeurs neuroendocrines, Departement de Recherche Translation- tumors and stable disease at initial diagnosis; (ii) or a "top-down" 2 nelle et Innovation, Centre Leon Berard, Lyon, France. INSERM U1052/CNRS strategy with a first-line cytotoxic chemotherapy for more aggres- UMR5286/Universite de Lyon, Lyon1 UMR-S1052, Centre de Recherche en 3 sive pNETs. Streptozotocin (STZ)-based chemotherapy, either Cancerologie, Lyon, France. Plateforme Anatomopathologie-Recherche, fl Departement de Recherche Translationnelle et Innovation, Centre Leon Berard, with doxorubicin or 5- uorouracil (5-FU), remains the standard Lyon, France. 4Service Central d'Anatomie et Cytologie Pathologiques, Hospices first-line chemotherapy showing a 40% response rate (2, 3). The Civils de Lyon, Hopital^ Edouard Herriot, Lyon, France. 5Universite de Lyon, novel targeted therapies sunitinib (4) and everolimus (5) have Universite Claude Bernard Lyon 1, Villeurbanne cedex, France. 6Service de improved the progression-free survival in two phase III clinical pathologie morphologique et moleculaire, Departement de biologie et patho- trials, but the objective response rate did not exceed 10%. New logie medicales; AMMICa, Inserm US23/CNRS UMS3655, Gustave Roussy Cancer therapeutic strategies need thus to be developed in order to Campus, Villejuif, France. 7FacultedeM edecine de Bicetre,^ Universite improve the management of patients with unresectable pNETs. Paris Sud, Universite Paris Saclay, Le Kremlin-Bicetre,^ France. 8Service d'hepatogastroent erologie et d'oncologie digestive, Hospices Civils de Lyon, In this context, combination therapies appear as promising Hopital^ Edouard Herriot, Lyon, France. options. Recent studies have evaluated the potential of such combi- natorial treatments in neuroendocrine tumors, including pNETs. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). mTOR inhibitors (everolimus or temsirolimus) were combined with SSAs in RADIANT-2 study (6) or with the anti-VEGF antibody T. Walter and C. Vercherat are co-senior authors of this article. bevacizumab (7). However, to date, limited numbers of phase I/II Corresponding Author: Cecile Vercherat, Centre Leon Berard, Neuroendocrine studies have evaluated the combination of mTOR inhibitor fl Tumor Group, Cheney B 3rd oor, 28 rue Laennec, Lyon 69008, France. Phone: with chemotherapy (8). Nevertheless, given (i) the low number 334-6985-6133; Fax: 0033478782955 E-mail: [email protected] of patients, (ii) the problem of safety when combining two types doi: 10.1158/1535-7163.MCT-17-0325 of treatment with their respective toxicity, and (iii) the growing Ó2017 American Association for Cancer Research. number of different combinatorial or sequential strategies to be 60 Mol Cancer Ther; 17(1) January 2018 Downloaded from mct.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 19, 2017; DOI: 10.1158/1535-7163.MCT-17-0325 mTOR Inhibition Synergizes with Chemotherapy evaluated, it is crucial to conduct studies with strong rationale and gift from B. Mark Evers, Galveston, TX, obtained in 2004) were to rely on in vitro and in vivo mechanistic studies, in order to better routinely culture in DMEM Glutamax/F-12K medium (1:1) sup- understand the benefit of combinations, evaluate their tolerance, plemented with 10% FBS and 1% penicillin/streptomycin. Rat and choose the best agents. radio-induced insulinoma, INS-1E cells (ref. 17; kind gift from For future studies, knowledge about mechanisms of resistance C. Wollheim and P. Maechler, Geneva, Switzerland, obtained should be taken in consideration when designing a new thera- in 2007) were routinely cultured in 5 mmol/L glucose RPMI peutic approach. On the one hand, chemotherapy has cytotoxic supplemented with 10% FBS, 10 mmol/L HEPES, 1 mmol/L effects which can be diminished by the activation of specific sodium pyruvate, 50 mmol/L b-mercaptoethanol, and 1% peni- survival and proliferation signaling pathways, leading to resis- cillin/streptomycin. MIN6 cells obtained from RIP-Tag mice tance. On the other hand, targeted therapies can inhibit these (kind gift from S. Dalle, Institut de Genomique Fonctionnelle, abnormally activated pathways; however, they do not necessarily Montpellier, France, obtained in 2009) were routinely cultured have a cytotoxic effect, leading to stabilization but low objective in 5 mmol/L glucose DMEM supplemented with 15% FBS, response. Based on these observations, we hypothesized that 50 mmol/L b-mercaptoethanol, and 1% penicillin/streptomycin. targeted therapies could prevent the activation of survival path- All cell lines were not authenticated and were obtained from ways and ultimately suppress chemoresistance. investigators who generated them. Upon reception, cells were Even if streptozotocin-based chemotherapy is the oldest cyto- amplified and early-passaged stocks were constituted. Cells were toxic chemotherapy used in pNETs, little is known about the passaged for fewer than three months after thawing. factors leading to resistance to streptozotocin in pNETs patients. Cellsweretestedforthepresenceofmycoplasma(MycoAlert O'Toole and colleagues showed that activation of the mTOR Mycoplasma Detection Kit; Lonza) on a regular basis (once a pathway was correlated with a low response to streptozotocin. month for in vitro experiments, and one day before injections in Indeed, in tumor tissues, high expression of AKT was correlated animals). with a lack of response to streptozotocin. On the opposite, conserved expression of PTEN (PI3K antagonist) was associated Reagents with response to streptozotocin (9). These observations are in Streptozotocin was purchased from Enzo Life Sciences. accordance with in vivo studies in which streptozotocin is mainly Everolimus was purchased from Selleck Chemicals. BKM120, used to induce diabetes in animal models. In pancreatic b cells, BEZ235, and MK-2206 were purchased from Active Biochem. specific deletion of Pten gene, as well as expression of constitu- For Western blot analysis, we used primary antibodies raised tively active AKT, protects animals from streptozotocin-induced against p-AKT(T308), p-AKT(S473), AKT, P70S6K, p-P70S6K diabetes and apoptosis (10, 11). It has been widely described that (T389), PRAS40, p-PRAS40(T246), 4EBP1, cleaved caspase-3, mTOR pathway activation has a central role in pNETs. At the p-HistoneH3(S10) (Cell Signaling Technology), p-4EBP1 genomic level, modifications of mTOR pathway coding genes (T45) (Abcam), and tubulin (Sigma). For IHC, we used pri- (PIK3CA, PTEN, TSC2) are involved in approximately 15% of mary antibodies directed to chromograninA
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