Reference Detail

Ref Type

Journal Article

PMID

(28843487)

Authors

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, null null

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Journal of investigative dermatology	138	1	2018 01	58-67	J Invest Dermatol

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
KIT	G565V	missense	unknown	KIT G565V lies within the cytoplasmic domain of the Kit protein (UniProt.org). G565V has been identified in the scientific literature (PMID: 28843487), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2023).
KIT	L576R	missense	unknown	KIT L576R lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 17372901). L576R has been identified in the scientific literature (PMID: 28843487, PMID: 28026870), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Jan 2024).
KIT	L631F	missense	unknown	KIT L631F lies within the protein kinase domain (exon 13) of the Kit protein (UniProt.org). L631F has been identified in the scientific literature (PMID: 28843487), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Jan 2024).
KIT	R634L	missense	unknown	KIT R634L lies within the protein kinase domain (exon 13) of the Kit protein (UniProt.org). R634L has been identified in the scientific literature (PMID: 28843487), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Apr 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT exon11	melanoma	sensitive	Nilotinib	Phase II	Actionable	In a Phase II trial, Tasigna (nilotinib) treatment resulted in complete response in 5% (1/19) and partial response in 21% (4/19) of melanoma patients harboring KIT exon 11 or exon 13 mutations (PMID: 28843487; NCT01168050).	28843487
KIT mutant	melanoma	sensitive	Nilotinib	Phase II	Actionable	In a Phase II trial, Tasigna (nilotinib) treatment resulted in complete response in 4% (1/25), durable partial response in 16% (4/25), and stable disease in 56% (14/25) of melanoma patients harboring KIT mutations (PMID: 28843487; NCT01168050).	28843487
KIT exon13	melanoma	sensitive	Nilotinib	Phase II	Actionable	In a Phase II trial, Tasigna (nilotinib) treatment resulted in complete response in 5% (1/19) and partial response in 21% (4/19) of melanoma patients harboring KIT exon 11 or exon 13 mutations (PMID: 28843487; NCT01168050).	28843487