Rapid and clinically significant response to masitinib in the treatment of mucosal primary esophageal melanoma with somatic KIT exon 11 mutation involving brain metastases: A case report

Prošvicová, Jarmila; Lukesová, S; Kopecký, J; Grim, Jiří; Papik, Zdenek; Kolarova, R.; Navratilova, Blanka; Dubreuil, Patrice; Agopian, Julie; Mansfield, Colin D.; Moussy, A.; Hermine, Olivier

doi:10.5507/bp.2015.061

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…15 In addition to imatinib, multikinase inhibitor sorafenib and newer-generation tyrosine kinase inhibitors such as nilotinib, dasatinib, and masitinib have shown some efficacy in metastatic mucosal melanomas harboring KIT exon 11 or 13 mutations. 38,39 However, development of resistance to c-Kit inhibition is common, 40 and although nilotinib may achieve temporary disease control in some imatinibresistant mucosal melanomas, 18 these examples illustrate limitations for c-Kit inhibitor-based therapy.…”

Section: Discussionmentioning

confidence: 99%

Identification of recurrent mutational events in anorectal melanoma

et al. 2017

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Anorectal melanoma is a rare disease that carries a poor prognosis. To date, limited genetic analyses confirmed KIT mutations as a recurrent genetic event similar to other mucosal melanomas, occurring in up to 30% of anorectal melanomas. Importantly, a subset of tumors harboring activating KIT mutations have been found to respond to c-Kit inhibitor-based therapy, with improved patient survival at advanced tumor stages. We performed comprehensive targeted exon sequencing analysis of 467 cancer-related genes in a larger series of 15 anorectal melanomas, focusing on potentially actionable variants based on gain- and loss-of-function mutations. We report the identification of oncogenic driver events in the majority (93%) of anorectal melanomas. These included variants in canonical MAPK pathway effectors rarely observed in cutaneous melanomas (including an HRAS mutation, as well as a BRAF mutation resulting in duplication of threonine 599), and recurrent mutations in the tumor suppressor NF1 in 20% of cases, which represented the second-most frequently mutated gene after KIT in our series. Furthermore, we identify SF3B1 mutations as a recurrent genetic event in mucosal melanomas. Our findings provide an insight into the genetic diversity of anorectal melanomas, and suggest significant potential for alternative targeted therapeutics in addition to c-Kit inhibitors for this melanoma subtype.

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Section: Discussionmentioning

confidence: 99%

Identification of recurrent mutational events in anorectal melanoma

et al. 2017

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“…For example, a patient with primary esophageal melanoma harboring KIT mutation in exon 11 showed significant response when being treated with oral masitinib. 73 Masitinib treatment caused dysphagia and odynophagia disappeared within 1 week and reduced size of brain metastatic lesions and visceral lesions in the following month. Another example is a 79-year-old man at stage IV M1b metastatic anal mucosal melanoma showing CR upon sorafenib therapy.…”

Section: Sunitinibmentioning

confidence: 97%

KIT and Melanoma: Biological Insights and Clinical Implications

2020

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OVERVIEW OF c-KIT AND ITS RTKs FAMILY c-KIT or CD117 is a member of class III transmembrane receptor tyrosine kinases (RTKs) along with platelet-derived growth factor receptors (PDGFRs), fms like tyrosine kinase 3 (FLT3)/ CD135, and macrophage colony stimulating factor receptors (M-CSFRs). It was discovered in 1987 as a cellular homologue of viral oncogene v-kit, which was isolated from a feline retro-virus. 1,2 A variety of cell types were identified to express c-KIT including hematopoietic cells, germ cells, gastrointestinal (GI) tract Cajal cells, melanoma cells, B cell progenitors, and mast cells. Wild-type c-KIT protein contains 976 amino acids (aa) divided into three main regions including an extracellular ligand-binding domain with 519 aa, a hydrophobic transmembrane domain with 23 aa, and an intracellular tail (Fig. 1). 3,4 The extracellular domain consists of five immunoglobulin-like domains D1-D5, in which D1-D3 is responsible for stem cell factor (SCF) binding while D4-D5 contains motif for receptor dimerization. The 433 aa cytoplasmic region includes a juxtamembrane domain and a tyrosine kinase domain with an insertion of approximately 80 residues. Most of phosphorylation sites on c-KIT are located at the juxta-membrane region, the kinase insertion domain, and the C-terminal tail. Human c-KIT is encoded by a proto-oncogene located on the chromosome 4 at position of q11-12. 5 This 90 kb gene is transcribed and translated into a core protein of 110 kDa, which is subsequently heterogeneously N-linked glycosylated, mainly in the extra

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“…Newer c- KIT TKIs, such as masitinib, sunitinib, dasatanib, and nilotinib, have shown modest efficacy, most notably in patients with tumors already resistant to imatinib [ 21 , 26 , 145 ]. A previous study found that masitinib caused tumor regression after brain metastasis in patients with c-KIT-mutant esophageal melanoma [ 146 ]. These treatment options should be studied further to better understand the cause of resistance [ 147 ].…”

Section: C-kitmentioning

confidence: 99%

Resistance to Molecularly Targeted Therapies in Melanoma

Patel

Eckburg

Gantiwala

et al. 2021

Cancers

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Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been developed against genetic biomarkers whose overexpression is implicated in tumorigenesis. The use of targeted therapies as an alternative or supplement to immunotherapy has revolutionized the management of metastatic melanoma. Although this treatment strategy is more efficacious and less toxic in comparison to traditional therapies, targeted therapies are less effective after prolonged treatment due to acquired resistance caused by mutations and activation of alternative mechanisms in melanoma tumors. Recent studies focus on understanding the mechanisms of acquired resistance to these current therapies. Further research is needed for the development of better approaches to improve prognosis in melanoma patients. In this article, various melanoma biomarkers including BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K are described, and their potential mechanisms for drug resistance are discussed.

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Rapid and clinically significant response to masitinib in the treatment of mucosal primary esophageal melanoma with somatic KIT exon 11 mutation involving brain metastases: A case report

Cited by 8 publications

References 11 publications

Identification of recurrent mutational events in anorectal melanoma

Identification of recurrent mutational events in anorectal melanoma

KIT and Melanoma: Biological Insights and Clinical Implications

Resistance to Molecularly Targeted Therapies in Melanoma

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