Pathology Outlines

Stains & CD markers
KIT

Authors: Joshua R. Bradish, M.D., Liang Cheng, M.D.

Last author update: 1 March 2014

Last staff update: 18 June 2021

Copyright: 2014-2024, PathologyOutlines.com, Inc.

PubMed Search: KIT[TI] melanoma mutations free full text[sb]

See also: CD117

Table of Contents

Cite this page: Bradish, J. KIT. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainskit.html. Accessed December 26th, 2024.

Definition / general

KIT is the gene encoding a transmembrane tyrosine kinase receptor, involved in both the MAP kinase and AKT pathways, which are intimately involved with cell proliferation and survival (J Clin Oncol 2013;31:3176, Int J Biol Sci 2013;9:435)
KIT activation occurs after binding of stem cell factor (SCF), a hematopoietic cytokine
Binding of SCF leads to dimerization of 2 KIT receptors, leading to downstream signal transduction
KIT is necessary for the normal development of melanocytes
KIT mutations occur in melanoma subtypes (see table below)

Diagrams / tables

Images hosted on other servers:

KIT dimerization

MAP kinase and AKT pathways

KIT mutations in melanoma subtypes

Mutations

KIT mutations are found in only 3% of melanomas overall
A disproportionate amount of KIT aberrations are identified in melanoma arising from chronically sun damaged skin, acral and mucosal sites (23% overall)
KIT mutations are rarely found in melanoma arising on nonchronically sun damaged skin (those melanomas containing frequent BRAF mutations) (J Clin Oncol 2013;31:3176)
Types of KIT mutations include: K642E*, L576P*, D816H, V559A, A829P, intronic deletion, R634W, Y553N and N566D (* two most common mutations)
KIT mutations are nearly always mutually exclusive with NRAS or BRAF

Associated histological findings

In general, the 3 types of melanomas enriched with KIT mutations (acral, mucosal and those with chronic sun damage) typically show a lentiginous growth pattern with single melanocytes distributed along the basal epidermis (J Invest Dermatol 2010;130:20)

Detection methods

KIT mutation detection is difficult because there is a wide range of possible, nonrecurring aberrations (J Clin Oncol 2013;31:3176)
Aberrations include: increased copy number, amplification or specific mutations
Specific mutations are only detectible through sequencing of relevant exons (9, 11, 13, 17 and 18) (Clin Cancer Res 2012;18:1195)
For melanoma, using CD117 as a marker for KIT overexpression is NOT reliable and should NOT be used
To date, there has been no significant discordance between primary and metastatic KIT melanomas

Inhibitor therapy

KIT testing is recommended after a mucosal or acral melanoma has been determined to be BRAF- (Clin Cancer Res 2012;18:1195, J Clin Oncol 2013;31:3176)
Sequencing of exons 9, 11, 13, 17 and 18 is performed
Imatinib is a tyrosine kinase inhibitor used to treat multiple neoplasms including: CML (Ph+), advanced GIST, ALL (Ph+), DFSP and others
Evidence from multiple phase II trials suggests that only certain KIT mutations, specifically those in exon 11 and exon 13, are responsive to inhibitor therapy, while others are not
Exon 11 contains the mutation L576P while exon 13 contains K642E; these are the 2 most commonly identified KIT mutations in melanoma
Ipilimumab, a monoclonal antibody which targets CTLA4, is another drug which shows some promise in melanomas known to be enriched with KIT mutations, and has been approved by the EU as a second line treatment of melanoma
Ipilimumab decreases inhibition of cytotoxic T cells and increases their ability to destroy cancer cells

Mechanisms of resistance

Resistance mechanisms in melanoma have not been well documented as the evaluation of imatinib is only in phase II trials
Criteria defining resistance have not been established (J Clin Oncol 2012;30:e37, J Invest Dermatol 2010;130:20)
In GIST, up to 50% of patients treated with imatinib develop resistance
Resistance mechanisms include: tyrosine kinase switching, resistance in wild type KIT, amplification and overexpression, efflux of imatinib by cells and acquired secondary KIT mutations
Secondary mutations in KIT are the most common mechanisms by which GISTs acquire resistance, typically through interefering with the drug binding site or activating a different locus of the receptor (J Clin Oncol 2006;24:4764, J Invest Dermatol 2010;130:20)
Future studies and clinical trials will evaluate responses with KIT inhibitors

Resistance therapies

Patients with GIST who demonstrate resistance on imatinib are either treated with dose escalation or an alternative tyrosine kinase inhibitor (J Invest Dermatol 2010;130:20)
Sunitinib is effective in KIT mutations, especially those with exon 9 mutations, V654A and T670I mutations (Clin Cancer Res 2006;12:2622)
Other KIT inhibitors used include nilotinib, dasatinib and sorafenib

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