STAT3 mediates Nilotinib response in KIT-altered Melanoma: a Phase II Multicenter Trial of the French Skin Cancer Network.

Fiche publication


Date publication

août 2017

Journal

The Journal of investigative dermatology

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DALAC Sophie


Tous les auteurs :
Delyon J, Chevret S, Jouary T, Dalac S, Dalle S, Guillot B, Arnault JP, Avril MF, Bedane C, Bens G, Pham-Ledard A, Mansard S, Grange F, Machet L, Meyer N, Legoupil D, Saiag P, Idir Z, Renault V, Deleuze JF, Hindie E, Battistella M, Dumaz N, Mourah S, Lebbe C,

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 melanomas harboring KIT alteration. The primary endpoint was the response rate (complete response (CR) or partial response (PR) following RECIST 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 4 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 3 persisting (3.6 and 2.8 years for 2 patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in STAT3 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 rational for future research assessing STAT inhibitors in KIT-mutated melanoma.

Mots clés

Administration, Oral, Aged, Antineoplastic Agents, pharmacology, Cell Line, Tumor, Cell Proliferation, drug effects, Exons, genetics, Female, Humans, Male, Melanoma, drug therapy, Middle Aged, Mutation, Phosphorylation, drug effects, Proto-Oncogene Proteins c-kit, antagonists & inhibitors, Pyrimidines, pharmacology, STAT3 Transcription Factor, metabolism, Signal Transduction, drug effects, Skin Neoplasms, drug therapy, Treatment Outcome

Référence

J. Invest. Dermatol.. 2017 Aug;: