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For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and\n                    <jats:italic>SDHB<\/jats:italic>\n                    knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant\n                    <jats:italic>SSTR2<\/jats:italic>\n                    and\n                    <jats:italic>SSTR1<\/jats:italic>\n                    expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST\n                    <jats:sub>2<\/jats:sub>\n                    agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST\n                    <jats:sub>2<\/jats:sub>\n                    -dependent manner, but only in\n                    <jats:italic>SDHB<\/jats:italic>\n                    knocked-down PPGL cells. Indeed, only\n                    <jats:italic>SDHB<\/jats:italic>\n                    KD cells showed stronger membrane-enriched SST\n                    <jats:sub>2<\/jats:sub>\n                    and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00440-5","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T01:53:11Z","timestamp":1775181191000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functional profiling of somatostatin receptors identifies somatostatin receptor subtype 2 as a vulnerability in Succinate Dehydrogenase SDHB-deficient pheochromocytomas and paragangliomas"],"prefix":"10.1186","volume":"7","author":[{"given":"V\u00edctor","family":"Garc\u00eda-Vioque","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Pedraza-Arevalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Trinidad","family":"Moreno-Montilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Rivero-Cort\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Bl\u00e1zquez-Encinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Mangili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Arroba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aura D.","family":"Herrera-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Culler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda \u00c1ngeles","family":"G\u00e1lvez-Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Barlier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa Mar\u00eda","family":"Botella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6256-5902","authenticated-orcid":false,"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3145-7287","authenticated-orcid":false,"given":"Justo P.","family":"Casta\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4649-0095","authenticated-orcid":false,"given":"Alejandro","family":"Ib\u00e1\u00f1ez-Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"440_CR1","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1056\/NEJMra1806651","volume":"381","author":"HPH Neumann","year":"2019","unstructured":"Neumann HPH, Young WF, Eng C. 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The study was approved by the Bioethics Committee of the Medical University of Cordoba\/IMIBIC (protocol code PI19\/01603, v1\u201413\/03\/2019) and Ethics Committees from all the Hospitals involved in the study. Informed consent from each patient was obtained through the Andalusian Biobank (Servicio Andaluz de Salud). Mice xenograft experiments were performed according to the European Regulations for Animal Care, in accordance with guidelines and regulations, and under the approval of the University of Cordoba research ethics committees (ref. 23\/09\/2022\/115).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"M.D.C. is a former employee of IPSEN. The rest of the authors have no relevant financial or non-financial interests to disclose, no competing interests to declare that are relevant to the content of this article, no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript and no financial or proprietary interests in any material discussed in this article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"44"}}