The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanoma
Abstract The nongenetic mechanisms required to control tumor phenotypic plasticity and shape drug‐resistance remain unclear. We show here that the Aryl hydrocarbon Receptor (AhR) transcription factor directly regulates the gene expression program associated with the acquisition of resistance to BRAF...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2022-12-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202215677 |
| _version_ | 1797283994790789120 |
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| author | Anaïs Paris Nina Tardif Francesca M Baietti Cyrille Berra Héloïse M Leclair Eleonora Leucci Marie‐Dominique Galibert Sébastien Corre |
| author_facet | Anaïs Paris Nina Tardif Francesca M Baietti Cyrille Berra Héloïse M Leclair Eleonora Leucci Marie‐Dominique Galibert Sébastien Corre |
| author_sort | Anaïs Paris |
| collection | DOAJ |
| description | Abstract The nongenetic mechanisms required to control tumor phenotypic plasticity and shape drug‐resistance remain unclear. We show here that the Aryl hydrocarbon Receptor (AhR) transcription factor directly regulates the gene expression program associated with the acquisition of resistance to BRAF inhibitor (BRAFi) in melanoma. In addition, we show in melanoma cells that canonical activation of AhR mediates the activation of the SRC pathway and promotes the acquisition of an invasive and aggressive resistant phenotype to front‐line BRAFi treatment in melanoma. This nongenetic reprogramming identifies a clinically compatible approach to reverse BRAFi resistance in melanoma. Using a preclinical BRAFi‐resistant PDX melanoma model, we demonstrate that SRC inhibition with dasatinib significantly re‐sensitizes melanoma cells to BRAFi. Together we identify the AhR/SRC axis as a new therapeutic vulnerability to trigger resistance and warrant the introduction of SRC inhibitors during the course of the treatment in combination with front‐line therapeutics to delay BRAFi resistance. |
| first_indexed | 2024-03-07T17:41:40Z |
| format | Article |
| id | doaj.art-18e95c983816457ca7f883a9359acf88 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:41:40Z |
| publishDate | 2022-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-18e95c983816457ca7f883a9359acf882024-03-02T16:02:02ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-12-011412n/an/a10.15252/emmm.202215677The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanomaAnaïs Paris0Nina Tardif1Francesca M Baietti2Cyrille Berra3Héloïse M Leclair4Eleonora Leucci5Marie‐Dominique Galibert6Sébastien Corre7Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR6290, ERL U1305 Rennes FranceUniv Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR6290, ERL U1305 Rennes FranceLaboratory for RNA Cancer Biology, Department of Oncology LKI, KU Leuven Leuven BelgiumUniv Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR6290, ERL U1305 Rennes FranceUniv Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR6290, ERL U1305 Rennes FranceLaboratory for RNA Cancer Biology, Department of Oncology LKI, KU Leuven Leuven BelgiumUniv Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR6290, ERL U1305 Rennes FranceUniv Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR6290, ERL U1305 Rennes FranceAbstract The nongenetic mechanisms required to control tumor phenotypic plasticity and shape drug‐resistance remain unclear. We show here that the Aryl hydrocarbon Receptor (AhR) transcription factor directly regulates the gene expression program associated with the acquisition of resistance to BRAF inhibitor (BRAFi) in melanoma. In addition, we show in melanoma cells that canonical activation of AhR mediates the activation of the SRC pathway and promotes the acquisition of an invasive and aggressive resistant phenotype to front‐line BRAFi treatment in melanoma. This nongenetic reprogramming identifies a clinically compatible approach to reverse BRAFi resistance in melanoma. Using a preclinical BRAFi‐resistant PDX melanoma model, we demonstrate that SRC inhibition with dasatinib significantly re‐sensitizes melanoma cells to BRAFi. Together we identify the AhR/SRC axis as a new therapeutic vulnerability to trigger resistance and warrant the introduction of SRC inhibitors during the course of the treatment in combination with front‐line therapeutics to delay BRAFi resistance.https://doi.org/10.15252/emmm.202215677BRAFi resistancecell plasticityexpressionmelanoma |
| spellingShingle | Anaïs Paris Nina Tardif Francesca M Baietti Cyrille Berra Héloïse M Leclair Eleonora Leucci Marie‐Dominique Galibert Sébastien Corre The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanoma EMBO Molecular Medicine BRAFi resistance cell plasticity expression melanoma |
| title | The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanoma |
| title_full | The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanoma |
| title_fullStr | The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanoma |
| title_full_unstemmed | The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanoma |
| title_short | The AhR‐SRC axis as a therapeutic vulnerability in BRAFi‐resistant melanoma |
| title_sort | ahr src axis as a therapeutic vulnerability in brafi resistant melanoma |
| topic | BRAFi resistance cell plasticity expression melanoma |
| url | https://doi.org/10.15252/emmm.202215677 |
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