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Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma (H021)

ABSTRACT: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. Here, we used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.578_579del) as actionable target in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Molecularly guided treatment with imatinib resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. This observation highlights the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscores that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.H021

PROVIDER: EGAS00001001845 | EGA |

REPOSITORIES: EGA

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Sequential Imatinib and Anti-PD-1 Therapy in KIT-Altered Melanoma: Mechanistic Insights and Clinical Benefit

Project description:KIT is a key oncogenic driver in triple-wildtype melanoma and represents a rational therapeutic target for KIT inhibitors such as imatinib. However, the tumor immune microenvironment in KIT-altered melanoma and optimal strategies to integrate immunotherapy remain poorly defined. In this study, we found that melanomas harboring KIT mutations or amplifications exhibited reduced CD8⁺ T cell infiltration, indicative of an immune-cold phenotype. Imatinib treatment reversed this Immunosuppressive microenvironment by enhancing CD8⁺ T cell infiltration and cytotoxic activity. Furthermore, imatinib upregulated O-GlcNAc transferase (OGT), which functions as a protein lactyltransferase and increased PD-L1 expression through lysine lactylation, thereby sensitizing tumors to anti–PD-1 therapy. Based on these findings, we conducted an open-label, single-arm phase II clinical trial in patients with advanced or metastatic KIT-altered melanoma. Patients received imatinib monotherapy as induction for six weeks, followed by combination therapy with toripalimab, an anti–PD-1 antibody. The combiniation therapy was well-tolerated and demonstrated encouraging clinical activity, with an objective response rate (ORR) of 59.4% in the overall cohort, 73.9% in patients with exon 11/13 mutations, and 100% in those with exon 11 mutation plus amplification—markedly higher than the ORRs of 23.3% with imatinib monotherapy and 25.7% with anti–PD-1 monotherapy. Median progression-free survival and overall survival were 8.2 months (95% CI, 6.5–9.9) and 15.1 months (95% CI, 13.1–20.8), respectively. These results support the use of imatinib as an immune-sensitizing induction therapy prior to PD-1 blockade in KIT-altered melanoma and highlight the therapeutic relevance of OGT-mediated PD-L1 regulation.

2026-07-23 | GSE303456 | GEO

Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations

Project description:Abstract: Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design

2006-01-10 | GSE4001 | GEO

A Retrospective Study of C-kit Mutation Status in Asian Patients With Advanced Gastro-intestinal Stromal Tumors (GIST) Treated With Imatinib.

Project description:Imatinib is the current standard treatment for advanced GIST. Previous studies have shown that GIST genotype was associated with treatment outcomes with exon 11 having superior outcome compared with exon 9 or WT.10, 11 In patients with exon 9 kit mutation, the response rate was higher at when imatinib was given at 800mg daily compared with the standard dose of 400mg daily. Although the data linking tyrosine kinase mutation status and imatinib response in metastatic GISTs is intriguing, more information is needed before mutation testing is adopted as part of the routine analysis of high-risk or overtly malignant KIT-expressing GISTs.25 Despite the fact that exon 9 mutations are associated with a lower response rate, overall survival does not appear to be better with high-dose therapy. The investigators propose to conduct a retrospective analysis of mutational analysis on patients with GIST and determine the relationship between patient response and imatinib dose.

| 2097070 | ecrin-mdr-crc

Affymetrix human DMET Plus array in GIST patients treated with imatinib

Project description:To understand the contribution of germline DNA polymorphisms discriminating between imatinib clinical outcome and toxicity, 38 GIST patients (all with KIT exon 11 mutation) treated with imatinib were analyzed through Affymetrix human DMET Plus array.

2019-01-01 | GSE119558 | GEO

Expression profiling of GIST: CD133 is associated with KIT exon 11 deletion, gastric location and poor prognosis

Project description:Background & Aims: In gastrointestinal stromal tumors (GIST) KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profile of GIST carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Methods: Expression profiling was performed on 9 tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analysed by meta-analysis. Differentially expressed genes were identified and confirmed by qPCR. Expression of CD133 (prominin-1) protein (AC133) was also examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in Western Sweden. Survival analysis was performed using Cox regression model. Results: Gene expression profiling, meta-analysis and qPCR demonstrated up-regulation of the stem cell marker CD133 in GIST carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was frequent in gastric GIST (48%) versus small intestinal GIST (4%). CD133 positivity was also frequent in GIST with KIT exon 11 mutations (41%) compared to tumors with mutations in KIT exon 9, PDGFRA, or wild-type tumors (0-17%). There was no significant correlation between CD133 staining and NIH risk score. Survival analysis demonstrated significant correlation between presence of CD133 and shorter overall survival. Conclusions: The stem cell marker CD133 is expressed in a subset of predominantly gastric GIST with KIT exon 11 mutations and associated with poor prognosis.

2010-06-30 | GSE14755 | GEO

Molecular comparison of imatinib-naïve and resistant gastrointestinal stromal tumors: differentially expressed microRNAs and mRNAs

Project description:Despite the success of imatinib in advanced gastrointestinal stromal tumor (GIST) patients, 50% of the patients experience resistance within two years of treatment underscoring the need to get better insight into the mechanisms conferring imatinib resistance. Here the microRNA and mRNA expression profiles in primary (imatinib-naïve) and imatinib-resistant GIST were examined. Fifty-three GIST samples harboring primary KIT mutations (exon 9; n=11/exon 11; n=41/exon 17; n=1) and comprising imatinib-naïve (IM-n) (n=33) and imatinib-resistant (IM-r) (n=20) tumors, were analyzed. The microRNA expression profiles were determined and from a subset (IM-n, n=14; IM-r, n=15) the mRNA expression profile was established. Ingenuity pathway analyses were used to unravel biochemical pathways and gene networks in IM-r GIST. Thirty-five differentially expressed miRNAs between IM-n and IM-r GIST samples were identified. Additionally, miRNAs distinguished IM-r samples with and without secondary KIT mutations. Furthermore 352 aberrantly expressed genes were found in IM-r samples. Pathway and network analyses revealed an association of differentially expressed genes with cell cycle progression and cellular proliferation thereby implicating genes and pathways involved in imatinib resistance in GIST. Differentially expressed miRNAs and mRNAs between IM-n and IM-r GIST were identified. Bioinformatic analyses provided insight into the genes and biochemical pathways involved in imatinib-resistance and highlighted key genes that may be putative treatment targets.

2019-06-12 | GSE132542 | GEO

Imatinib targeting of KIT-mutant oncoprotein in melanoma

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

Imatinib Treatment of GIST882

Project description:Gastrointestinal Stromal Tumor frequently harbor mutations in the KIT receptor tyrosine kinase and depend on its activity for growth. This underlies the efficacy of imatinib, a inhibitor of KIT activity, in GIST management. GIST882 is a patient derived GIST cell line that harbor a K640E exon 13 KIT mutation and is sensitive to imatinib treatment. To analyze the downstream effect of KIT inhibition, GIST882 cells were treated for 8 hours with 1μM Imatinib.

2010-10-13 | GSE22433 | GEO

Somatic Activation of KIT in Distinct Subtypes of Melanoma

Project description:Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogenactivated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% ofmucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden. Keywords: melanoma, oncogene, comparative genomic hybridization, KIT

2006-09-09 | GSE4747 | GEO

Mast cell microRNAs regulated by KIT signaling

Project description:Objective is to identify microRNAs regulated by KIT signaling in mast cells. miRNA profiles of murine bone marrow derived mast cells with and without SCF treatment were compared. In addition, miRNA profiles of the P815 mutant KIT cell line with and without the KIT inhibitor, imatinib, were compared. We identified miRNAs that were differentially regulated by KIT signals.

2011-01-25 | GSE26783 | GEO

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