STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network - Université de Montpellier Accéder directement au contenu
Article Dans Une Revue Journal of Investigative Dermatology Année : 2018

STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network

1 Service de Dermatologie [AP-HP Hôpital Saint-Louis]
2 (CIC-BT 301) - CIC - Biotherapie - Saint Louis
3 IDO (U976 / UMR_S 976) - Immunologie, dermatologie, oncologie ; Oncodermatologie, immunologie et cellules souches cutanées
4 Service de biostatistiques et information médicale [Saint-Louis]
5 CH Pau
6 Service de Dermatologie (CHU de Dijon)
7 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
8 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
9 Pathogénèse et contrôle des infections chroniques (PCCI)
10 Service de dermatologie [CHU d'Amiens-Picardie]
11 Service de Dermatologie [CHU Cochin]
12 UPD5 - Université Paris Descartes - Paris 5
13 Service d'Oncologie médicale [CHU Limoges]
14 CHRO - Centre Hospitalier Régional d'Orléans
15 Service de dermatologie [Bordeaux]
16 CHU Clermont-Ferrand
17 Hôpital universitaire Robert Debré [Reims]
18 Service de dermatologie (CHRU de Tours)
19 iBraiN - Imaging, Brain & Neuropsychiatry
20 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
21 Dermato - BREST - Service de dermatologie
22 BECCOH - Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie
23 Hôpital Ambroise Paré [AP-HP]
24 Département de la Recherche Clinique et du Développement
25 Fondation Jean Dausset CEPH
26 CNG - Centre National de Génotypage
27 Service de médecine nucléaire [Bordeaux]
28 UB - Université de Bordeaux
29 UMR 1165 - Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique
30 Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
31 Hôpital Saint-Louis
Thomas Jouary
Sophie Dalac

Résumé

Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma.

Dates et versions

hal-01983526 , version 1 (16-01-2019)

Identifiants

Citer

Julie Delyon, Sylvie Chevret, Thomas Jouary, Sophie Dalac, Stéphane Dalle, et al.. STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network. Journal of Investigative Dermatology, 2018, 138 (1), pp.58-67. ⟨10.1016/j.jid.2017.07.839⟩. ⟨hal-01983526⟩
184 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More