{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:49:12Z","timestamp":1790254152156,"version":"4.1.0"},"reference-count":85,"publisher":"The Endocrine Society","issue":"11","funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC\/Transregio 205\/1"],"award-info":[{"award-number":["CRC\/Transregio 205\/1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>There are no officially approved therapies for metastatic pheochromocytomas apart from ultratrace 131I-metaiodbenzylguanidine therapy, which is approved only in the United States. We have, therefore, investigated the antitumor potential of molecular-targeted approaches in murine pheochromocytoma cell lines [monocyte chemoattractant protein (MPC)\/monocyte chemoattractant protein\/3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], immortalized mouse chromaffin Sdhb\u2212\/\u2212 cells, three-dimensional pheochromocytoma tumor models (MPC\/MTT spheroids), and human pheochromocytoma primary cultures. We identified the specific phosphatidylinositol-3-kinase \u03b1 inhibitor BYL719 and the mammalian target of rapamycin inhibitor everolimus as the most effective combination in all models. Single treatment with clinically relevant doses of BYL719 and everolimus significantly decreased MPC\/MTT and Sdhb\u2212\/\u2212 cell viability. A targeted combination of both inhibitors synergistically reduced MPC and Sdhb\u2212\/\u2212 cell viability and showed an additive effect on MTT cells. In MPC\/MTT spheroids, treatment with clinically relevant doses of BYL719 alone or in combination with everolimus was highly effective, leading to a significant shrinkage or even a complete collapse of the spheroids. We confirmed the synergism of clinically relevant doses of BYL719 plus everolimus in human pheochromocytoma primary cultures of individual patient tumors with BYL719 attenuating everolimus-induced AKT activation. We have thus established a method to assess molecular-targeted therapies in human pheochromocytoma cultures and identified a highly effective combination therapy. Our data pave the way to customized combination therapy to target individual patient tumors.<\/jats:p>","DOI":"10.1210\/en.2019-00410","type":"journal-article","created":{"date-parts":[[2019,8,5]],"date-time":"2019-08-05T09:15:57Z","timestamp":1564996557000},"page":"2600-2617","source":"Crossref","is-referenced-by-count":37,"title":["Synergistic Highly Potent Targeted Drug Combinations in Different Pheochromocytoma Models Including Human Tumor Cultures"],"prefix":"10.1210","volume":"160","author":[{"given":"Maria","family":"Fankhauser","sequence":"first","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Bechmann","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lauseker","sequence":"additional","affiliation":[{"name":"Institute for Medical Information Sciences, Biometry, and Epidemiology, Campus Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Goncalves","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, UMR970, Paris-Cardiovascular Research Center, Equipe Labellis\u00e9e par la Ligue contre le Cancer, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, Facult\u00e9 de M\u00e9decine, Paris, France"},{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Favier","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, UMR970, Paris-Cardiovascular Research Center, Equipe Labellis\u00e9e par la Ligue contre le Cancer, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, Facult\u00e9 de M\u00e9decine, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Klink","sequence":"additional","affiliation":[{"name":"Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany"},{"name":"National Center of Genetics, Laboratoire National de Sant\u00e9, Dudelange, Luxembourg"},{"name":"German Cancer Consortium, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doreen","family":"William","sequence":"additional","affiliation":[{"name":"German Cancer Consortium, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gieldon","sequence":"additional","affiliation":[{"name":"Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany"},{"name":"German Cancer Consortium, Dresden, Germany"},{"name":"German Cancer Research Center, Heidelberg, Germany"},{"name":"Core Unit for Molecular Tumor Diagnostics, National Center for Tumor Diseases, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Maurer","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Sp\u00f6ttl","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Rank","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kn\u00f6sel","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Orth","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian G","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke Tatjana","family":"Aristizabal Prada","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Rubinstein","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Fassnacht","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division of Endocrinology and Diabetology, University Hospital, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Spitzweg","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley B","family":"Grossman","sequence":"additional","affiliation":[{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom"},{"name":"Royal Free Hospital ENETS Centre of Excellence, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Pacak","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Beuschlein","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"},{"name":"Klinik f\u00fcr Endokrinologie, Diabetologie und Klinische Ern\u00e4hrung, Universit\u00e4tsspital Z\u00fcrich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan R","family":"Bornstein","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Eisenhofer","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at Technische Universit\u00e4t Dresden, Dresden, Germany"},{"name":"Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph J","family":"Auernhammer","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Reincke","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7064-590X","authenticated-orcid":false,"given":"Svenja","family":"N\u00f6lting","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2019,7,19]]},"reference":[{"issue":"5","key":"2019101610285403300_bib1","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1097\/00000658-197405000-00029","article-title":"Current management of pheochromocytoma","volume":"179","author":"Remine","year":"1974","journal-title":"Ann Surg"},{"issue":"4","key":"2019101610285403300_bib2","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/BF00353738","article-title":"\u201cThe\u201d pheochromocytoma: a benign, intra-adrenal, hypertensive, sporadic unilateral tumor. Does it exist","volume":"18","author":"Proye","year":"1994","journal-title":"World J Surg"},{"issue":"6","key":"2019101610285403300_bib3","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1097\/00000658-199906000-00001","article-title":"Clinical experience over 48 years with pheochromocytoma","volume":"229","author":"Goldstein","year":"1999","journal-title":"Ann Surg"},{"issue":"6","key":"2019101610285403300_bib4","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1530\/eje.0.1410619","article-title":"Pheochromocytoma in Italy: a multicentric retrospective study","volume":"141","author":"Mannelli","year":"1999","journal-title":"Eur J Endocrinol"},{"issue":"4","key":"2019101610285403300_bib5","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0090-4295(98)00612-8","article-title":"Pheochromocytomas: can malignant potential be predicted","volume":"53","author":"John","year":"1999","journal-title":"Urology"},{"issue":"3","key":"2019101610285403300_bib6","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1053\/ejso.2002.1413","article-title":"The management of benign and malignant pheochromocytoma and abdominal paraganglioma","volume":"29","author":"Edstr\u00f6m Elder","year":"2003","journal-title":"Eur J Surg Oncol"},{"issue":"4","key":"2019101610285403300_bib7","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1210\/jc.2004-1398","article-title":"Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma","volume":"90","author":"Amar","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2019101610285403300_bib8","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.juro.2010.12.050","article-title":"Predictive factors for malignant pheochromocytoma: analysis of 136 patients","volume":"185","author":"Feng","year":"2011","journal-title":"J Urol"},{"issue":"4","key":"2019101610285403300_bib9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.4111\/kju.2011.52.4.241","article-title":"Predictive characteristics of malignant pheochromocytoma","volume":"52","author":"Park","year":"2011","journal-title":"Korean J Urol"},{"issue":"5","key":"2019101610285403300_bib10","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/cen.13434","article-title":"Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis","volume":"87","author":"Hamidi","year":"2017","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2019101610285403300_bib11","article-title":"Peptide receptor radionuclide therapy as a novel treatment for metastatic and invasive phaeochromocytoma and paraganglioma","author":"Mak","journal-title":"Neuroendocrinology"},{"issue":"2-3","key":"2019101610285403300_bib12","first-page":"117","article-title":"Metastatic phaeochromocytoma: spinning towards more promising treatment options","volume":"127","author":"N\u00f6lting","year":"2019","journal-title":"Exp Clin Endocrinol Diabetes"},{"issue":"10","key":"2019101610285403300_bib13","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/nrm.2017.53","article-title":"The multifaceted roles of PARP1 in DNA repair and chromatin remodelling","volume":"18","author":"Ray Chaudhuri","year":"2017","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"14","key":"2019101610285403300_bib14","doi-asserted-by":"crossref","first-page":"7303","DOI":"10.1073\/pnas.94.14.7303","article-title":"Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells","volume":"94","author":"de Murcia","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"issue":"14","key":"2019101610285403300_bib15","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1158\/1078-0432.CCR-17-3406","article-title":"Targeting NAD+\/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma","volume":"24","author":"Pang","year":"2018","journal-title":"Clin Cancer Res"},{"issue":"4","key":"2019101610285403300_bib16","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1159\/000430816","article-title":"Temozolomide in advanced neuroendocrine neoplasms: pharmacological and clinical aspects","volume":"101","author":"Koumarianou","year":"2015","journal-title":"Neuroendocrinology"},{"key":"2019101610285403300_bib17","doi-asserted-by":"crossref","first-page":"138573","DOI":"10.1155\/2015\/138573","article-title":"Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis","volume":"2015","author":"Luchetti","year":"2015","journal-title":"Int J Endocrinol"},{"issue":"20","key":"2019101610285403300_bib18","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1093\/hmg\/ddr324","article-title":"Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma","volume":"20","author":"Burnichon","year":"2011","journal-title":"Hum Mol Genet"},{"issue":"1","key":"2019101610285403300_bib19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.trecan.2017.11.001","article-title":"Genomic landscape of pheochromocytoma and paraganglioma","volume":"4","author":"Jochmanova","year":"2018","journal-title":"Trends Cancer"},{"key":"2019101610285403300_bib20","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1055\/s-0029-1220687","article-title":"Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001)","volume":"41","author":"Druce","year":"2009","journal-title":"Horm Metab Res"},{"issue":"11","key":"2019101610285403300_bib21","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.1210\/jc.2012-2356","article-title":"Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas","volume":"97","author":"Ayala-Ramirez","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"196","key":"2019101610285403300_bib22","doi-asserted-by":"crossref","first-page":"196ra99","DOI":"10.1126\/scitranslmed.3005747","article-title":"mTORC1 inhibition is required for sensitivity to PI3K p110\u03b1 inhibitors in PIK3CA-mutant breast cancer","volume":"5","author":"Elkabets","year":"2013","journal-title":"Sci Transl Med"},{"issue":"20","key":"2019101610285403300_bib23","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1056\/NEJMoa1813904","article-title":"Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer","volume":"380","author":"Andr\u00e9","year":"2019","journal-title":"N Engl J Med"},{"issue":"10","key":"2019101610285403300_bib24","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1530\/ERC-18-0159","article-title":"The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance","volume":"25","author":"Aristizabal Prada","year":"2018","journal-title":"Endocr Relat Cancer"},{"issue":"3","key":"2019101610285403300_bib25","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s004410000290","article-title":"Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice","volume":"302","author":"Powers","year":"2000","journal-title":"Cell Tissue Res"},{"issue":"3","key":"2019101610285403300_bib26","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s10585-009-9236-0","article-title":"Characterization of an animal model of aggressive metastatic pheochromocytoma linked to a specific gene signature","volume":"26","author":"Martiniova","year":"2009","journal-title":"Clin Exp Metastasis"},{"issue":"2","key":"2019101610285403300_bib27","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1530\/JME-12-0028","article-title":"Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines","volume":"49","author":"N\u00f6lting","year":"2012","journal-title":"J Mol Endocrinol"},{"issue":"1","key":"2019101610285403300_bib28","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s10616-013-9545-7","article-title":"Mouse cell line authentication","volume":"66","author":"Almeida","year":"2014","journal-title":"Cytotechnology"},{"issue":"6","key":"2019101610285403300_bib29","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.ccr.2013.04.018","article-title":"SDH mutations establish a hypermethylator phenotype in paraganglioma","volume":"23","author":"Letouz\u00e9","year":"2013","journal-title":"Cancer Cell"},{"issue":"5","key":"2019101610285403300_bib30","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1111\/bcp.12834","article-title":"Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis","volume":"81","author":"Budde","year":"2016","journal-title":"Br J Clin Pharmacol"},{"issue":"3","key":"2019101610285403300_bib31","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/bcp.12378","article-title":"Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies","volume":"78","author":"De Buck","year":"2014","journal-title":"Br J Clin Pharmacol"},{"issue":"1","key":"2019101610285403300_bib32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1200\/JCO.2005.02.2194","article-title":"Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer","volume":"24","author":"Faivre","year":"2006","journal-title":"J Clin Oncol"},{"issue":"1","key":"2019101610285403300_bib33","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s40262-015-0295-x","article-title":"Population pharmacokinetic model of cabozantinib in patients with medullary thyroid carcinoma and its application to an exposure-response analysis","volume":"55","author":"Miles","year":"2016","journal-title":"Clin Pharmacokinet"},{"issue":"4","key":"2019101610285403300_bib34","doi-asserted-by":"crossref","DOI":"10.1101\/pdb.prot087379","article-title":"Crystal violet assay for determining viability of cultured cells","volume":"2016","author":"Feoktistova","year":"2016","journal-title":"Cold Spring Harb Protoc"},{"issue":"5","key":"2019101610285403300_bib35","doi-asserted-by":"crossref","first-page":"E172","DOI":"10.3390\/md16050172","article-title":"Anti-tumorigenic and anti-metastatic activity of the sponge-derived marine drugs aeroplysinin-1 and isofistularin-3 against pheochromocytoma in vitro","volume":"16","author":"Bechmann","year":"2018","journal-title":"Mar Drugs"},{"issue":"5","key":"2019101610285403300_bib36","doi-asserted-by":"crossref","first-page":"594","DOI":"10.3390\/cancers11050594","article-title":"Impact of extrinsic and intrinsic hypoxia on catecholamine biosynthesis in absence or presence of Hif2\u03b1 in pheochromocytoma cells","volume":"11","author":"Bechmann","year":"2019","journal-title":"Cancers (Basel)"},{"issue":"3-4","key":"2019101610285403300_bib37","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1159\/000439431","article-title":"Cabozantinib and tivantinib, but not INC280, induce antiproliferative and antimigratory effects in human neuroendocrine tumor cells in vitro: evidence for \u2018off-target\u2019 effects not mediated by c-Met inhibition","volume":"103","author":"Reuther","year":"2016","journal-title":"Neuroendocrinology"},{"key":"2019101610285403300_bib38","unstructured":"RRID:AB_2315049, https:\/\/scicrunch.org\/resolver\/RRID:AB_2315049."},{"key":"2019101610285403300_bib39","unstructured":"RRID:AB_329827, https:\/\/scicrunch.org\/resolver\/RRID:AB_329827."},{"key":"2019101610285403300_bib40","unstructured":"RRID:AB_330947, https:\/\/scicrunch.org\/resolver\/RRID:AB_330947."},{"key":"2019101610285403300_bib41","unstructured":"RRID:AB_2097841, https:\/\/scicrunch.org\/resolver\/RRID:AB_2097841."},{"key":"2019101610285403300_bib42","unstructured":"RRID:AB_10695803, https:\/\/scicrunch.org\/resolver\/RRID:AB_10695803."},{"key":"2019101610285403300_bib43","unstructured":"RRID:AB_2259616, https:\/\/scicrunch.org\/resolver\/RRID:AB_2259616."},{"key":"2019101610285403300_bib44","unstructured":"RRID:AB_2070801, https:\/\/scicrunch.org\/resolver\/RRID:AB_2070801."},{"key":"2019101610285403300_bib45","unstructured":"RRID:AB_330944, https:\/\/scicrunch.org\/resolver\/RRID:AB_330944."},{"key":"2019101610285403300_bib46","unstructured":"RRID:AB_390722, https:\/\/scicrunch.org\/resolver\/RRID:AB_390722."},{"key":"2019101610285403300_bib47","unstructured":"RRID:AB_10694233, https:\/\/scicrunch.org\/resolver\/RRID:AB_10694233."},{"key":"2019101610285403300_bib48","unstructured":"RRID:AB_331355, https:\/\/scicrunch.org\/resolver\/RRID:AB_331355."},{"key":"2019101610285403300_bib49","unstructured":"RRID:AB_329830, https:\/\/scicrunch.org\/resolver\/RRID:AB_329830."},{"key":"2019101610285403300_bib50","unstructured":"RRID:AB_10547140, https:\/\/scicrunch.org\/resolver\/RRID:AB_10547140."},{"key":"2019101610285403300_bib51","unstructured":"RRID:AB_2074795, https:\/\/scicrunch.org\/resolver\/RRID:AB_2074795."},{"key":"2019101610285403300_bib52","unstructured":"RRID:AB_2080320, https:\/\/scicrunch.org\/resolver\/RRID:AB_2080320."},{"key":"2019101610285403300_bib53","unstructured":"RRID:AB_2536328, https:\/\/scicrunch.org\/resolver\/RRID:AB_2536328."},{"key":"2019101610285403300_bib54","unstructured":"RRID:AB_2533767, https:\/\/scicrunch.org\/resolver\/RRID:AB_2533767."},{"key":"2019101610285403300_bib55","unstructured":"RRID:AB_476744, https:\/\/scicrunch.org\/resolver\/RRID:AB_476744."},{"key":"2019101610285403300_bib56","unstructured":"RRID:AB_95187, https:\/\/scicrunch.org\/resolver\/RRID:AB_95187."},{"issue":"6","key":"2019101610285403300_bib57","doi-asserted-by":"crossref","first-page":"E809","DOI":"10.3390\/cancers11060809","article-title":"Optimizing genetic workup in pheochromocytoma and paraganglioma by integrating diagnostic and research approaches","volume":"11","author":"Gieldon","year":"2019","journal-title":"Cancers (Basel)"},{"key":"2019101610285403300_bib58","unstructured":"Fankhauser\n              M\n            , BechmannN, LausekerM, GoncalvesJ, FavierJ, KlinkB, WilliamD, GieldonL, MaurerJ, Sp\u00f6ttlG, RankP, Kn\u00f6selT, OrthM, ZieglerCG, Aristizabal PradaET, RubinsteinG, FassnachtM, SpitzwegC, GrossmanAB, PacakK, BeuschleinF, BornsteinSR, EisenhoferG, AuernhammerCJ, ReinckeM, N\u00f6ltingS. Data from: Synergistic highly potent targeted drug combinations in different pheochromocytoma models including human tumor cultures. Secure Synology Webstorage NAS 2019. Deposited 7 May 2019. https:\/\/emds-nas.quickconnect.to\/d\/s\/496975158882345550\/sUrm8NYh5szKPD5NacKzaoXM18OrpRiV-TyKA5VWc5QY_."},{"issue":"8","key":"2019101610285403300_bib59","doi-asserted-by":"crossref","first-page":"e1006248","DOI":"10.1371\/journal.pgen.1006248","article-title":"Identification and functional testing of ERCC2 mutations in a multi-national cohort of patients with familial breast- and ovarian cancer","volume":"12","author":"Rump","year":"2016","journal-title":"PLoS Genet"},{"issue":"4","key":"2019101610285403300_bib60","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1006\/jmcc.1998.0655","article-title":"The statistics of synergism","volume":"30","author":"Slinker","year":"1998","journal-title":"J Mol Cell Cardiol"},{"issue":"7","key":"2019101610285403300_bib61","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1242\/jcs.138057","article-title":"GSK-3: at the crossroads of cell death and survival","volume":"127","author":"Maurer","year":"2014","journal-title":"J Cell Sci"},{"issue":"18","key":"2019101610285403300_bib62","doi-asserted-by":"crossref","first-page":"15641","DOI":"10.1074\/jbc.M208984200","article-title":"Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1\/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells","volume":"278","author":"Pirola","year":"2003","journal-title":"J Biol Chem"},{"issue":"4","key":"2019101610285403300_bib63","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1159\/000481887","article-title":"GSK3\u03b1\/\u03b2: a novel therapeutic target for neuroendocrine tumors","volume":"106","author":"Aristizabal Prada","year":"2018","journal-title":"Neuroendocrinology"},{"issue":"3","key":"2019101610285403300_bib64","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1210\/jc.2006-2315","article-title":"Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas","volume":"92","author":"Timmers","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"issue":"9808","key":"2019101610285403300_bib65","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/S0140-6736(11)61742-X","article-title":"Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study","volume":"378","author":"Pavel","year":"2011","journal-title":"Lancet"},{"issue":"6","key":"2019101610285403300_bib66","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1056\/NEJMoa1009290","article-title":"Everolimus for advanced pancreatic neuroendocrine tumors","volume":"364","author":"Yao","year":"2011","journal-title":"N Engl J Med"},{"issue":"10022","key":"2019101610285403300_bib67","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/S0140-6736(15)00817-X","article-title":"Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study","volume":"387","author":"Yao","year":"2016","journal-title":"Lancet"},{"issue":"7","key":"2019101610285403300_bib68","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1210\/jc.2004-2198","article-title":"AKT is highly phosphorylated in pheochromocytomas but not in benign adrenocortical tumors","volume":"90","author":"Fassnacht","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2019101610285403300_bib69","doi-asserted-by":"crossref","first-page":"336","DOI":"10.7150\/thno.7851","article-title":"PI3K-AKT-mTOR-signaling and beyond: the complex network in gastroenteropancreatic neuroendocrine neoplasms","volume":"4","author":"Briest","year":"2014","journal-title":"Theranostics"},{"issue":"1","key":"2019101610285403300_bib70","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1159\/000336089","article-title":"Translation of molecular pathways into clinical trials of neuroendocrine tumors","volume":"97","author":"Pavel","year":"2013","journal-title":"Neuroendocrinology"},{"issue":"3","key":"2019101610285403300_bib71","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1158\/0008-5472.CAN-05-2925","article-title":"mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt","volume":"66","author":"O\u2019Reilly","year":"2006","journal-title":"Cancer Res"},{"issue":"9","key":"2019101610285403300_bib72","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer","volume":"118","author":"Carracedo","year":"2008","journal-title":"J Clin Invest"},{"issue":"1","key":"2019101610285403300_bib73","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.canlet.2010.02.018","article-title":"Compensatory activation of Akt in response to mTOR and Raf inhibitors: a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease","volume":"295","author":"Zitzmann","year":"2010","journal-title":"Cancer Lett"},{"issue":"18","key":"2019101610285403300_bib74","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1002\/cncr.26011","article-title":"Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1\/2 and AKT","volume":"117","author":"Svejda","year":"2011","journal-title":"Cancer"},{"issue":"14","key":"2019101610285403300_bib75","doi-asserted-by":"crossref","first-page":"5381","DOI":"10.18632\/oncotarget.2111","article-title":"Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition","volume":"5","author":"Passacantilli","year":"2014","journal-title":"Oncotarget"},{"issue":"8","key":"2019101610285403300_bib76","doi-asserted-by":"crossref","first-page":"e0182852","DOI":"10.1371\/journal.pone.0182852","article-title":"The selective PI3K\u03b1 inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models","volume":"12","author":"N\u00f6lting","year":"2017","journal-title":"PLoS One"},{"issue":"10","key":"2019101610285403300_bib77","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/35096075","article-title":"The renaissance of GSK3","volume":"2","author":"Cohen","year":"2001","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2019101610285403300_bib78","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.2741\/3324","article-title":"GSK-3 inhibitors and insulin receptor signaling in health, disease, and therapeutics","volume":"14","author":"Wada","year":"2009","journal-title":"Front Biosci"},{"issue":"1","key":"2019101610285403300_bib79","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12935-015-0162-8","article-title":"Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI\/MSS status","volume":"15","author":"Genther Williams","year":"2015","journal-title":"Cancer Cell Int"},{"issue":"6","key":"2019101610285403300_bib80","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1080\/14656566.2017.1297423","article-title":"Niraparib for the treatment of ovarian cancer","volume":"18","author":"Kanjanapan","year":"2017","journal-title":"Expert Opin Pharmacother"},{"issue":"4","key":"2019101610285403300_bib81","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/cncr.29089","article-title":"Clinical next-generation sequencing in patients with non-small cell lung cancer","volume":"121","author":"Hagemann","year":"2015","journal-title":"Cancer"},{"issue":"24","key":"2019101610285403300_bib82","doi-asserted-by":"crossref","first-page":"8573","DOI":"10.1073\/pnas.0503224102","article-title":"The NF1 tumor suppressor critically regulates TSC2 and mTOR [published correction appears in Proc Natl Acad Sci USA. 2005;102(44):16119]","volume":"102","author":"Johannessen","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"2019101610285403300_bib83","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.cub.2007.11.066","article-title":"TORC1 is essential for NF1-associated malignancies","volume":"18","author":"Johannessen","year":"2008","journal-title":"Curr Biol"},{"issue":"4","key":"2019101610285403300_bib84","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/0092-8674(90)90150-D","article-title":"The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21","volume":"63","author":"Martin","year":"1990","journal-title":"Cell"},{"issue":"4","key":"2019101610285403300_bib85","doi-asserted-by":"crossref","first-page":"C13","DOI":"10.1530\/ERC-13-0046","article-title":"The NF1 gene: a frequent mutational target in sporadic pheochromocytomas and beyond","volume":"20","author":"Welander","year":"2013","journal-title":"Endocr Relat Cancer"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/en.2019-00410\/28953515\/en.2019-00410.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/160\/11\/2600\/30157541\/en.2019-00410.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/160\/11\/2600\/30157541\/en.2019-00410.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T17:06:43Z","timestamp":1571245603000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/160\/11\/2600\/5535649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,19]]},"references-count":85,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2019,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2019-00410","relation":{},"ISSN":["1945-7170"],"issn-type":[{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,11]]},"published":{"date-parts":[[2019,7,19]]}}}