TERT Expression Induces Resistance to BRAF and MEK Inhibitors in BRAF-Mutated Melanoma In Vitro.

Autor:	Delyon J; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.; Département de Dermatologie, Hôpital Saint Louis, AP-HP, F-75010 Paris, France., Vallet A; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France., Bernard-Cacciarella M; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.; Département de Dermatologie, Hôpital Saint Louis, AP-HP, F-75010 Paris, France., Kuzniak I; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France., Reger de Moura C; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.; Département de Pharmacogénomique, Hôpital Saint Louis, AP-HP, F-75010 Paris, France., Louveau B; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.; Département de Pharmacogénomique, Hôpital Saint Louis, AP-HP, F-75010 Paris, France., Jouenne F; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.; Département de Pharmacogénomique, Hôpital Saint Louis, AP-HP, F-75010 Paris, France., Mourah S; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.; Département de Pharmacogénomique, Hôpital Saint Louis, AP-HP, F-75010 Paris, France., Lebbé C; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.; Département de Dermatologie, Hôpital Saint Louis, AP-HP, F-75010 Paris, France., Dumaz N; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), F-75010 Paris, France.
Jazyk:	angličtina
Zdroj:	Cancers [Cancers (Basel)] 2023 May 24; Vol. 15 (11). Date of Electronic Publication: 2023 May 24.
DOI:	10.3390/cancers15112888
Abstrakt:	Because BRAF-mutated melanomas are addicted to the Mitogen Activated Protein Kinase (MAPK) pathway they show a high response rate to BRAF and MEK inhibitors. However, the clinical responses to these inhibitors are often short-lived with the rapid onset of resistance to treatment. Deciphering the molecular mechanisms driving resistance has been the subject of intense research. Recent in vitro and clinical data have suggested a link between expression of telomerase and resistance to targeted therapy in melanoma. TERT promoter mutations are the main mechanism for the continuous upregulation of telomerase in melanoma and co-occur frequently with BRAF alterations. To understand how TERT promoter mutations could be associated with resistance to targeted therapy in melanoma, we conducted translational and in vitro studies. In a cohort of V600E-BRAF-mutated melanoma patients, we showed that the TERT promoter mutation status and TERT expression tended to be associated with response to BRAF and MEK inhibitors. We demonstrated that TERT overexpression in BRAF-mutated melanoma cells reduced sensitivity to BRAF and MEK independently of TERT's telomer maintenance activity. Interestingly, inhibition of TERT reduced growth of BRAF-mutated melanoma including resistant cells. TERT expression in melanoma can therefore be a new biomarker for resistance to MAPK inhibitors as well as a novel therapeutic target.
Databáze:	MEDLINE
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