Importance of the AhR/Src axis in the reprogramming of metastatic melanoma
Gene Expression and Oncogenesis team, under the direction of Sebastien Corre.
Melanoma is the most deadly form of skin cancer. In nearly half of all cases, tumor cells carry the BRAFV600 mutation, which causes constitutive activation of the MAPK pathway that promotes tumor growth. The presence of this mutation makes patients eligible for targeted therapies: BRAF inhibitors (BRAFi). The use of BRAFi, in combination with MEK inhibitors, rapidly produces an impressive response in patients. Unfortunately, in the majority of cases, resistance mechanisms develop and lead to patient relapse. The tumor heterogeneity and high plasticity of melanoma cells allow them to rapidly adapt to treatment following the progressive emergence of resistant tumor cells. Previous work performed in the laboratory demonstrated that canonical activation of AhR induces the expression of genes involved in the acquisition of BRAFi resistance. We now report that AhR activation leads to the activation of its partner, the Src oncoprotein. Activation of this AhR/Src axis induces reprogramming of melanoma cells to an aggressive, invasive and dedifferentiated phenotypic state. Conversely, the inhibition of the AhR/Src axis allows the reversal of the cells towards a sensitive program. We have also shown, via a PDX model of resistant melanoma tumors, that the use of Src inhibitors allows the resensitization of melanoma cells to BRAF inhibition. Taken together, this work highlights the hope of a new therapeutic option for patients.
- Robert Ballotti DR, INSERM U1065, C3M, Rapporteur
- Lionel Larue DR, INSERM U1021, CNRS UMR3347, Rapporteur
- Samia Mourah PU, INSERM UMRS 976 Univ. Paris-Diderot, Examinatrice
- Xavier Coumoul PU, INSERM UMR-S 1124, T3S, Examinateur,
- Anne Corlu DR, CNRS NUMECAN, Equipe Express, Examinatrice
- Marie-Dominique Galibert PU-PH, IGDR UMR6290 UR1-CNRS, Examinatrice
- Sébastien Corre CR, IGDR UMR 6290 UR1-CNRS, Directeur de thèse