• GIST
• KIT
• autophosphorylation
• c-kit
• canine
• loss-of-function mutation

• 19K06390 KAKENHI scientific research grants

• Humans
• Sunitinib/therapeutic use
• Middle Aged
• Proto-Oncogene Proteins c-kit/genetics
• Male
• Female
• Adult
• Aged
• Mutation
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/adverse effects
• Neoplasms/drug therapy
• Neoplasms/genetics

• UG1 CA189869 NCI NIH HHS
• UG1 CA233341 NCI NIH HHS
• UG1 CA233302 NCI NIH HHS
• UG1 CA233180 NCI NIH HHS
• U10 CA180820 NCI NIH HHS
• U10 CA180794 NCI NIH HHS

• KIT proto-oncogene
• canine mast cell tumors
• internal tandem duplications
• single nucleotide variants

• DOR1827892 University of Padua

• KIT D816H
• KIT D816V-negative
• KIT D816Y
• KIT mutation-negative
• advanced systemic mastocytosis

• Barzolvolimab
• KIT
• briquilimab
• chronic inducible urticaria
• chronic spontaneous urticaria
• chronic urticaria
• mast cell
• tyrosine kinases

• Humans
• Omalizumab/adverse effects
• Anti-Allergic Agents/adverse effects
• Chronic Disease
• Chronic Urticaria/drug therapy
• Chronic Urticaria/chemically induced
• Urticaria/drug therapy
• Urticaria/chemically induced
• Immunosuppressive Agents/therapeutic use
• Chronic Inducible Urticaria

• CD28 Antigens/genetics
• CD28 Antigens/metabolism
• Cell Line, Tumor
• Immunotherapy, Adoptive
• Interleukin-2/pharmacology
• Interleukin-2/metabolism
• Receptor Protein-Tyrosine Kinases
• T-Lymphocytes
• Proto-Oncogene Proteins c-kit/metabolism

• P30 CA008748 NCI NIH HHS
• R01 CA235667 NCI NIH HHS
• R01 CA236615 NCI NIH HHS
• U01 CA214195 NCI NIH HHS

• ASXL1
• D816V
• DNMT3A
• EZH2
• KIT
• RUNX1
• SRSF2
• mutations
• prognostic
• systemic mastocytosis

• Epigenetics
• Inflammation

• angiogenesis
• mast cells
• melanoma
• tumor microenevironment
• tumor progression

• Adult
• Autocrine Communication
• Disease Progression
• Disease Susceptibility
• Female
• Humans
• Immunohistochemistry
• Immunophenotyping
• Male
• Mast Cells/immunology
• Mast Cells/metabolism
• Melanoma/etiology
• Melanoma/metabolism
• Melanoma/pathology
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Paracrine Communication
• Proto-Oncogene Proteins c-kit/metabolism
• Skin Neoplasms/etiology
• Skin Neoplasms/metabolism
• Skin Neoplasms/pathology
• Stem Cell Factor/metabolism
• Tumor Microenvironment
• Melanoma, Cutaneous Malignant

There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10^-9), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.

In a prespecified interim analysis of a pivotal phase 2 trial, avapritinib, a selective KIT inhibitor, elicited robust clinical and molecular responses, was generally well tolerated and led to improved patient-reported outcomes in patients with advanced systemic mastocytosis.

Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 10⁹/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

In a phase 1 trial of patients with advanced systemic mastocytosis, avapritinib, a selective KIT inhibitor, was generally well tolerated, elicited durable clinical responses and led to reductions in mast cell disease burden.

• autoimmunity
• cancer
• mast cell
• multiple sclerosis
• rheumatoid arthritis
• type 1 diabetes

Melanoma causes the highest mortality rate among all skin cancers. However, the underlying molecular mechanisms leading to metastasis and poor prognosis in melanoma have not been fully elucidated. In this study, the differentially expressed genes (DEGs) related to metastasis in melanoma were screened out. The results of gene annotation was combined with The Cancer Genome Atlas (TCGA) database. The microRNA (miRNA) network that regulates key genes and their correlation with BRAF^V600E was preliminarily analyzed. Cell and molecular biology experiments were conducted to verify the results of bioinformatics analysis. Results showed that the PI3K-Akt signaling pathway contained the key genes CDK2, CDK4, KIT, and Von Willebrand factor. Survival analysis showed that high expression of the four key genes significantly reduced the survival rate of patients with melanoma. Correlation analysis showed that BRAF^V600E may regulate the expression of the four key genes, and a total of 240 miRNAs may regulate this expression. Experiments showed that the inactivation of key genes inhibits the proliferation, migration, and invasion of melanoma. In conclusion, the PI3K-Akt signaling pathway and the four key genes promoted the proliferation, migration, and invasion of melanoma, and related to poor prognosis of patients with melanoma.

• bioinformatics
• melanoma
• regulatory analysis
• signaling pathway
• survival analysis

• hypomethylating agents
• immunotherapy
• myelodysplastic syndromes
• targeted therapy
• treatment resistance

• Antineoplastic Agents/therapeutic use
• Combined Modality Therapy/methods
• DNA Methylation/drug effects
• Humans
• Immunotherapy/methods
• Molecular Targeted Therapy/methods
• Myelodysplastic Syndromes/drug therapy
• Myelodysplastic Syndromes/immunology
• Myelodysplastic Syndromes/therapy
• Treatment Outcome

• KIT
• clonality
• mast cell
• mast cell activation syndrome
• mastocytosis
• mutations

• Antihistamine
• Histamine
• Mast cell
• Neurological symptom
• Systemic mastocytosis
• Vertigo

• KIT variants
• gene polymorphisms
• hereditary alpha-tryptasemia
• mast cell activation syndrome
• mast cells
• prognostication

• Cytokines/genetics
• Humans
• Interleukin-13/genetics
• Interleukin-6/genetics
• Interleukins/genetics
• Mast Cells/pathology
• Mastocytosis, Systemic/diagnosis
• Mastocytosis, Systemic/genetics
• Mastocytosis, Systemic/metabolism
• Mastocytosis, Systemic/physiopathology
• Nerve Tissue Proteins/genetics
• Phospholipase C gamma/genetics
• Polymorphism, Genetic
• Proto-Oncogene Proteins c-kit/genetics
• Proto-Oncogene Proteins c-kit/metabolism
• Receptors, G-Protein-Coupled/genetics
• Receptors, Neuropeptide/genetics
• Toll-Like Receptor 2/genetics
• Toll-Like Receptor 2/metabolism

• Gleich syndrome
• episodic angioedema with eosinophilia syndrome
• hypereosinophilia
• hypereosinophilic syndromes
• imatinib mesylate

• Angioedema/chemically induced
• Angioedema/drug therapy
• Eosinophilia/drug therapy
• Humans
• Imatinib Mesylate
• Male
• Prednisone/therapeutic use
• Syndrome

• KIT
• gene polymorphisms
• prognostication
• tryptase

• ATP-Binding Cassette Transporters/genetics
• Adolescent
• Adult
• Aged
• Cytochrome P-450 CYP2B6/genetics
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Humans
• Male
• Mastocytosis/genetics
• Mastocytosis/pathology
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Otx Transcription Factors/genetics
• Polymorphism, Single Nucleotide/genetics
• Proto-Oncogene Proteins c-kit/genetics
• RNA, Long Noncoding/genetics
• S100 Proteins/genetics
• Young Adult

• P32470, F4701-B20 and F4704-B20 Austrian Science Fund (FWF)
• POIG Grant 01.01.02-10-005/08 TESTOPLEK Popoulous collection founded by European Regional Development Fund
• DIR/WK/2017/01 Polish Ministry of Science
• P 32470 Austrian Science Fund FWF
• ST 02-0066/07/253 and ST 02-0141/07/231 Polish Ministry of Sciences and Education

Laparoscopy induces adhesion due to ischemia-reperfusion injury. However, the detail pathomechanism is poorly understood. This study aimed to investigate the impact of laparoscopy on mast cell and mesothelium morphological changes in the rat.

Forty-nine males of Sprague-Dawley Rattus norvegicus were divided into four groups: a) control and b) intervention groups P1, P2, and P3 that underwent 60 min laparoscopic using carbon dioxide (CO₂) insufflation at 8, 10, and 12 mmHg groups, respectively. Serum hydrogen peroxide (H₂O₂), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and oxidative stress index (OSI) levels were determined 24 h after laparoscopy. Histopathological analyses of mast cell infiltration and degranulation and mesothelium thickness in the liver, greater omentum, mesenterium, small intestine, and peritoneum were performed 7 days after the procedure.

H₂O₂, MDA, and OSI levels were significantly increased in the intervention groups compared with the control (p<0.05), while the SOD and CAT levels were decreased in the intervention groups compared with the control (p<0.05). Mast cell infiltration and degranulation were higher in the intervention groups than in control (p<0.05), while the mesothelium thickness was significantly lower in the laparoscopic groups than in control (p<0.05). Interestingly, the decrease in mesothelium thickness was strongly associated with the increase in mast cell infiltration and degranulation (p<0.01).

Our study shows that laparoscopy in rats increases mast cell infiltration and degranulation, which also results in and correlates with a decrease in mesothelial thickness.

• Laparoscopic procedure
• Rattus norvegicus
• mast cell infiltration and degranulation
• mesothelium thickness
• oxidative stress

Systemic mastocytosis is a rare and heterogeneous disease characterized by mast cell proliferation and activation. KIT is a transmembrane tyrosine kinase which plays a key role in mast cell growth, differentiation and survival. After interaction with its ligand, the stem cell factor, KIT dimerizes activating downstream pathways involving multiple tyrosine kinases (PI3K, JAK/STAT, RAS/ERK). Activating mutations in KIT are detected in most cases of systemic mastocytosis, being the most common KIT D816V. Therefore, since the emergence of tyrosine kinase inhibitors, KIT inhibition has been an attractive approach when facing mastocytosis treatment. Initial reports showed that only the rare KIT D816V negative cases were responsive to tyrosine kinase inhibitors. However, the development of new tyrosine kinase inhibitors such as midostaurin or avapritinib with activity against mast cells carrying the D816V KIT mutation, has changed the landscape of this disease.

• KIT
• avapritinib
• cytoreductive therapy
• imatinib
• mast cell
• midostaurin
• systemic mastocytosis
• tyrosine kinase inhibitor

• KIT activating mutations
• advanced systemic mastocytosis
• mast cells
• stem cell transplantation
• tyrosine kinase inhibitors

• C-kit receptor
• clinical trials
• masitinib
• mast cells
• tyrosine kinase inhibitors

• Expression
• Feline iris melanoma
• Immunohistochemistry
• Oncogene
• Protein

• Anaphylaxis
• C-KIT
• Hymenoptera
• KIT mutation
• Mastocytosis

• Advanced disease
• Drug development
• KIT mutations
• Mast cells
• Mastocytosis
• Targeted drugs
• Tyrosine kinase inhibitors

• Bone marrow
• Cell purification
• Diagnosis
• Flow cytometry
• KIT mutation
• Mast cells
• Mastocytosis
• Prognosis

• KIT mutation
• hematopoietic precursor cells
• immunophenotype
• mast cell
• systemic mastocytosis

• KIT D816V mutant
• NSG mice
• ROSAKIT D816V cell line
• advanced systemic mastocytosis
• gluc reporter

Mastocytosis are rare diseases characterized by an accumulation of clonal mast cells (MCs) in one or multiple organs or tissues. Patients with systemic mastocytosis (SM), whose MCs frequently arbor the activating D816V KIT mutation, may have indolent to aggressive diseases, and they may experience MC mediator related symptoms. Indolent SM with recurrent anaphylaxis or vascular collapse in the absence of skin lesions, ISMs(−), is a specific subtype indolent SM (ISM), and this clonal MC activation disorder represents a significant fraction of all MC activation syndromes. The V560G KIT mutation is extremely rare in patients with SM and its biological and prognostic impact remains unknown.

A 15-year old boy was referred to our hospital because of repeated episodes of flushing, hypotension and syncope since the age of 3-years, preceded by skin lesions compatible with mastocytosis on histopathology that had disappeared in the late-early childhood. Diagnosis of ISM, more precisely the ISMs(−) variant, was confirmed based on the clinical manifestations together with increased baseline serum tryptase levels and the presence of morphologically atypical, mature appearing (CD117+high, FcεRI+) phenotypically aberrant (CD2+, CD25+) MCs, expressing activation-associated markers (CD63, CD69), in the bone marrow. Molecular genetic studies revealed the presence of the KIT V560G mutation in bone marrow MCs, but not in other bone marrow cells, whereas the screening for mutations in codon 816 of KIT was negative. The patient was treated with oral disodium cromoglycate and the disease had a favorable outcome after an eleven-year follow-up period, during which progressively lower serum tryptase levels together with the fully disappearance of all clinical manifestations was observed.

To the best of our knowledge this first report of a patient with ISM, whose bone marrow MCs carry the KIT V560G activating mutation, manifesting as recurrent spontaneous episodes of flushing and vascular collapse in the absence of skin lesions at the time of diagnosis, in whom disodium cromoglycate had led to long term clinical remission.

• Disodium cromoglycate
• KIT V560G mutation
• Mast cell activation disorders
• Mast cells
• Recurrent anaphylaxis
• Systemic mastocytosis

Somatic mutations of KIT are frequently found in mastocytosis and gastrointestinal stromal tumor (GIST), while germline mutations of KIT are rare, and only found in few cases of familial GIST and mastocytosis. Although ligand-independent activation is the common feature of KIT mutations, the phenotypes mediated by various germline KIT mutations are different. Germline KIT mutations affect different tissues such as interstitial cells of Cajal (ICC), mast cells or melanocytes, and thereby lead to GIST, mastocytosis, or abnormal pigmentation. In this review, we summarize germline KIT mutations in familial mastocytosis and GIST and discuss the possible cellular context dependent transforming activity of KIT mutations.

• Cancer
• KIT
• Signal transduction
• Targeted therapy

• Epigenesis, Genetic
• Family Characteristics
• Humans
• Inheritance Patterns/genetics
• Mast Cells/pathology
• Mastocytosis, Systemic/epidemiology
• Mastocytosis, Systemic/genetics
• Mastocytosis, Systemic/pathology
• Models, Biological

c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence.

• c-Kit
• cancer
• cancer therapy
• oncogene

• KIT mutation
• anaphylaxis
• mast cell
• mast cell activation syndrome
• mastocytosis
• tryptase