Lack of Response to Imatinib in Melanoma Carrying Rare KIT Mutation p.T632I.
Ontology highlight
ABSTRACT:
SUBMITTER: Orlova KV
PROVIDER: S-EPMC6477486 | biostudies-literature | 2019 Jan-Apr
REPOSITORIES: biostudies-literature
Publications
Lack of Response to Imatinib in Melanoma Carrying Rare <i>KIT</i> Mutation p.T632I.
Orlova Kristina V KV Yanus Grigory A GA Aleksakhina Svetlana N SN Venina Aigul R AR Iyevleva Aglaya G AG Demidov Lev V LV Imyanitov Evgeny N EN
Case reports in oncology 20190123 1
Approximately 15% of acral and mucous melanomas carry activating mutations in <i>KIT</i> oncogene. There is a diversity of spectrum of <i>KIT</i> mutations, with some of them rendering tumors responsive to imatinib, while others being imatinib-resistant or not studied yet. Here we present an acral melanoma patient with <i>KIT</i> р.T632I mutation, who failed to respond to imatinib. ...[more]
Similar Datasets
Project description:This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day(-1). In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ralpha and -Rbeta expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ralpha in seven out of 12 cases (58%) and for PDGF-Rbeta in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.
| S-EPMC2362005 | biostudies-literature
Project description:Metastatic melanoma is an aggressive treatment-refractory malignancy. Recently, c-Kit mutations were discovered in certain mucosal melanomas. A clinical trial was initiated with the c-Kit inhibitor imatinib mesylate. The first treated patient experienced dramatic clinical improvement within days, followed by major responses by PET/CT four weeks later at all sites of metastatic disease. Several established mucosal melanoma cell lines exhibited imatinib sensitivity in a fashion correlating with c-Kit mutational status. Although c-Kit mutations are uncommon in cutaneous melanoma, they may arise in geographically distinct subsets for whom use of c-Kit targeted kinase inhibition should be considered in a rational therapeutic approach. Keywords: Whole genome copy number analysis
2008-12-24 | GSE8164 | GEO
Project description:Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant disorder associated with mutations in the KIT gene in the majority of cases. Although, exon 11 appears to be the hot spot region for approximately 95% of germline mutations, pathogenic variations have also been identified in exon 8, 13 and 17. Exon 13 germline mutations are extremely rare amongst familial GISTs and seven families with a germline mutation have been reported to date. Moreover, the role of imatinib mesylate in this rare familiar settings is not completely known so far. We describe here clinical, imaging, pathological and genetic findings of a family with four affected members; grandmother, his son and two grand-sons having a germline gain-of-function mutation of KIT in exon 13 and discuss the imatinib mesylate treatment surveillance outcomes towards disease management.
| S-EPMC5658632 | biostudies-literature
Project description:Metastatic melanoma is an aggressive treatment-refractory malignancy. Recently, c-Kit mutations were discovered in certain mucosal melanomas. A clinical trial was initiated with the c-Kit inhibitor imatinib mesylate. The first treated patient experienced dramatic clinical improvement within days, followed by major responses by PET/CT four weeks later at all sites of metastatic disease. Several established mucosal melanoma cell lines exhibited imatinib sensitivity in a fashion correlating with c-Kit mutational status. Although c-Kit mutations are uncommon in cutaneous melanoma, they may arise in geographically distinct subsets for whom use of c-Kit targeted kinase inhibition should be considered in a rational therapeutic approach. Keywords: Whole genome copy number analysis Copy number analysis using high-density SNP arrays to investigate genetic gains and losses involved in the genesis of mucosal and cutaneous melanoma. GSE8164_raw_copy_number_calls.xls contains raw copy number calls generated by dChip (build 5/2007) for GIST, K008, K029, M34, MEL1, MEL40, M6, and 5 Affymetrix controls (copy number identity 2 i.e. normal), which are available on the HapMAP site.
2008-12-23 | E-GEOD-8164 | biostudies-arrayexpress
Project description:Neuroendocrine tumors (NET) and gastrointestinal stromal tumors (GIST) are believed to originate from the cells of Cajal that are randomly dispersed along the aerodigestive tract. Despite their distinct morphologic appearance, NET and GIST may share oncogenic mechanisms. Often presenting in the metastatic setting, treatment options for patients with NET are limited. This case report presents a patient with refractory metastatic NET that did not respond conventional chemotherapy. The patient was treated with a KIF11 inhibitor in a phase I clinical trial and experienced a prolonged and clinically meaningful partial response. On progression at 20 months, the patient's tumor was sequenced to reveal a KIT exon 11 mutation. Institution of imatinib therapy achieved a rapid and sustained antitumor effect with profound clinical benefit. Despite previously reported KIT expression in NET, this is the first documented case of an activating KIT mutation in NET and of successful treatment with both a KIF11 inhibitor and imatinib, each of which was elucidated through molecular profiling of the patient's tumor. Imatinib may be a valuable therapy in NET harboring activating KIT mutations.
| S-EPMC4112647 | biostudies-literature
Project description:BackgroundCanine malignant melanoma is highly aggressive and generally chemoresistant. Toceranib is a kinase inhibitor drug that inhibits several tyrosine kinases including the proto-oncogene receptor tyrosine kinase KIT. Although canine malignant melanoma cells often express KIT, a therapeutic effect for toceranib has yet to be reported for this tumor, with only a small number of patients studied to date. This is a case report of a dog with malignant melanoma that experienced a transient response to toceranib. Furthermore, the KIT expressed in the tumor of this case was examined using molecular analysis.Case presentationA Shiba Inu dog presented with a gingival malignant melanoma extending into surrounding structures with metastasis to a submandibular lymph node. The dog was treated with toceranib (Palladia®; 2.6-2.9 mg/kg, orally, every other day) alone. Improvement of tumor-associated clinical signs (e.g., halitosis, tumor hemorrhage, trismus, and facial edema) with reduced size of the metastatic lymph node was observed on Day 15. The gingival tumor and associated masses in the masseter and pterygoid muscles decreased in size by Day 29 of treatment. Toceranib treatment was terminated on Day 43 due to disease progression and the dog died on Day 54. The tumor of this dog had a novel deletion mutation c.1725_1733del within KIT and the mutation caused ligand-independent phosphorylation of KIT, which was suppressed by toceranib. This mutation was considered to be an oncogenic driver mutation in the tumor of this dog, thereby explaining the anti-tumor activity of toceranib.ConclusionsThis is the first report that presents a canine case of malignant melanoma that responded to toceranib therapy. KIT encoded by KIT harboring a mutation c.1725_1733del is a potential therapeutic target for toceranib in canine malignant melanoma. Further investigation of the KIT mutation status and toceranib therapy in canine malignant melanoma will need to be undertaken.
| S-EPMC8028755 | biostudies-literature
Project description:A 13-year-old spayed mixed-breed dog was diagnosed with a gastrointestinal stromal tumor (GIST) after histopathological examination of an abdominal mass. Five months after surgical resection of the tumor, we detected the recurrence of GIST with multiple disseminated abdominal lesions. A sequence analysis of cDNA obtained from a biopsy of the recurrent tumors revealed a mutation within exon 9 of the c-kit gene (1523A>T, Asn(508)Ile), which has been shown to cause ligand-independent phosphorylation of the KIT protein in GISTs and canine mast cell tumors (MCTs). Upon detection of the recurrent tumors, we initiated treatment with imatinib mesylate (10 mg/kg, q 24 hr). After 2 months, the dog achieved complete remission. Our findings indicate that canine GIST, and possibly MCT, may be responsive to molecular-targeted therapy.
| S-EPMC4667679 | biostudies-literature
Project description:Mutations in the activation segment of the v-raf murine sarcoma viral oncogene homolog B (BRAF) gene are present in approximately 50% of melanomas. The selective BRAF inhibitor vemurafenib has demonstrated significant clinical benefits in patients with melanomas harboring the most common mutations (V600E, V600K and V600R). However, the clinical activity of BRAF inhibitors in patients with rare mutations of codon 600 and the surrounding codons has not been documented.We used the BRAF inhibitor vemurafenib to treat a patient presenting a rare p.V600_K601delinsD-mutated melanoma. An objective response was evidenced by two months of progression-free survival. By cloning and sequencing BRAF exon 15, we confirmed that a dual mutation was present on a single allele and thus resulted in a BRAFV(600DK601del) mutant protein. We also performed an in silico crystal structure analysis of the mutated protein, in order to characterize the nature of the putative interaction between vemurafenib and the mutant protein.This clinical experience suggests that (i) patients with BRAFV(600DK601del)-mutation-positive melanoma can be treated successfully with the oral BRAF inhibitor vemurafenib and (ii) molecular screening in this context should encompass rare and complex mutations.
| S-EPMC4192296 | biostudies-literature
Project description:Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.
| S-EPMC6756115 | biostudies-literature
Project description:BackgroundGain-of-function mutations in KIT are driver events of oncogenesis in mast cell tumours (MCTs) affecting companion animals. Somatic mutations of KIT determine the constitutive activation of the tyrosine kinase receptor leading to a worse prognosis and a shorter survival time than MCTs harbouring wild-type KIT. However, canine MCTs carrying KIT somatic mutations generally respond well to tyrosine kinase inhibitors; hence their presence represents a predictor of treatment effectiveness, and its detection allows implementing a stratified medical approach. Despite this, veterinary oncologists experience treatment failures, even with targeted therapies whose cause cannot be elucidated. The first case of an MCT-affected dog caused by a secondary mutation in the tyrosine kinase domain responsible for resistance has recently been reported. The knowledge of this and all the other mutations responsible for resistance would allow the effective bedside implementation of a deeply stratified and more effective medical approach.Case presentationThe second case of a canine MCT carrying a different resistance mutation is herein described. The case was characterised by aggressive behaviour and early metastasis unresponsive to both vinblastine- and masitinib-based treatments. Molecular profiling of the tumoural masses revealed two different mutations; other than the already known activating mutation p.Asn508Ile in KIT exon 9, which is tyrosine kinase inhibitor-sensitive, a nearly adjacent secondary missense mutation, p.Ala510Val, which had never before been described, was detected. In vitro transfection experiments showed that the secondary mutation did not cause the constitutive activation by itself but played a role in conferring resistance to masitinib.ConclusionsThis study highlighted the importance of the accurate molecular profiling of an MCT in order to improve understanding of the molecular mechanism underlying tumourigenesis and reveal chemoresistance in MCTs for more effective therapies. The detection of the somatic mutations responsible for resistance should be included in the molecular screening of MCTs, and a systematic analysis of all the cases characterised by unexpected refractoriness to therapies should be investigated in depth at both the genetic and the phenotypic level.
| S-EPMC7029481 | biostudies-literature