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In melanoma, TGF\u03b2 signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGF\u03b2 signaling to elevated resistance to targeted therapy in melanoma, separate findings have indicated a favorable treatment response through TGF\u03b2-mediated increase of cell death. We now found that the outcome of TGF\u03b2 signaling in the context of targeted therapy is dose dependent. Unlike low doses, high levels of TGF\u03b2 signal activation induce apoptosis upon simultaneous MAPK pathway inhibition, even in targeted therapy resistant melanoma cell lines. Using transcriptomic analyses, combined with genomic target identification of the critical TGF\u03b2 signaling effector SMAD4, we demonstrate that parallel activation of TGF\u03b2 signaling and MAPK pathway inhibition causes a complete switch of TGF\u03b2 target genes from promoting pro-invasive processes to fueling pro-apoptotic pathways. Investigations of underlying mechanisms identified a novel apoptosis-inducing gene signature. Functional validation of signature members highlighted a central role of the pro-apoptotic BCL2 family member <jats:italic>BCL2L11<\/jats:italic> (BIM) in mediating apoptosis in this condition. Using a modified, synthetic version of the <jats:italic>TGFB1<\/jats:italic> mRNA for intra-tumoral injections, we additionally showcase a potential therapeutic application of this treatment combination.<\/jats:p>","DOI":"10.1038\/s41419-024-07305-1","type":"journal-article","created":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T16:18:56Z","timestamp":1734797936000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["TGF\u03b2 signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9359-9179","authenticated-orcid":false,"given":"Benjamin","family":"Loos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9847-5562","authenticated-orcid":false,"given":"Adrian","family":"Salas-Bastos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5868-4797","authenticated-orcid":false,"given":"Anna","family":"Nordin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7308-9777","authenticated-orcid":false,"given":"Julien","family":"Debbache","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salome","family":"Stierli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil F.","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Rufli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5355-3387","authenticated-orcid":false,"given":"Conrad","family":"Wyss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell P.","family":"Levesque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Dummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3155-1211","authenticated-orcid":false,"given":"Wendy Wei-Lynn","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2946-5576","authenticated-orcid":false,"given":"Steve","family":"Pascolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1547-5415","authenticated-orcid":false,"given":"Claudio","family":"Cant\u00f9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1143-7908","authenticated-orcid":false,"given":"Lukas","family":"Sommer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,21]]},"reference":[{"key":"7305_CR1","doi-asserted-by":"publisher","first-page":"487.","DOI":"10.3390\/biom10030487","volume":"10","author":"K Tzavlaki","year":"2020","unstructured":"Tzavlaki K, Moustakas A. 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