KIT and Melanoma: Biological Insights and Clinical Implications

Pham, Duc Minh; Guhan, Samantha; Tsao, Hensin

doi:10.3349/ymj.2020.61.7.562

Cited by 74 publications

(65 citation statements)

References 91 publications

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“…Mutations in c- KIT mostly occur in acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, c- KIT has been used in clinical trials of advanced melanoma to inhibit its function[ 9 - 11 ]. Based on these findings, this case met the above diagnostic criteria and was diagnosed as PMML.…”

Section: Discussionmentioning

confidence: 99%

Primary pulmonary malignant melanoma diagnosed with percutaneous biopsy tissue: A case report

Xi¹,

Huang²,

Xi³

et al. 2020

WJCC

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BACKGROUND Primary malignant melanoma of the lung (PMML) is a rare and highly malignant tumor with a poor prognosis. Here, we report a PMML case diagnosed by computed tomography (CT)-guided percutaneous biopsy, describe its pathological features and review relevant literature to improve our understanding of this tumor. CASE SUMMARY A 64-year-old Chinese female presented with productive cough for 7 mo. A chest CT scan showed a large and space-occupying lesion in Lingual lobe. Positron emission tomography-CT revealed multiple nodules located in the superior lobe apicoposterior segment of her left lung. Brain magnetic resonance imaging showed numerous enhancing nodules, suggesting brain metastasis. Abdominal CT scan did not show any abnormalities. By CT-guided percutaneous biopsy, four pieces of gray and taupe tissues (1 cm length and 0.1 mm in diameter) were obtained. After pathologic examination, the tumor was found to consist of epidermal and nested small round cells, fibrosis and thin-walled blood vessels. The finding was suggestive of malignant melanoma. To confirm the diagnosis, pathological morphology and immunophenotypic features of the biopsy specimens were observed. The patient denied any history of skin tumors. No abnormal lesions were detected in other sites of the body. Molecular testing was positive for wild-type EGFR and KIT gene mutations. Finally, the clinical and pathological findings suggested PMML. CONCLUSION PMML is very rare, and the percutaneous biopsy tissue is limited. Therefore, comprehensive consideration of histology, immunohistochemistry, imaging, and clinical information is important for the diagnosis of PMML.

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Section: Discussionmentioning

confidence: 99%

Primary pulmonary malignant melanoma diagnosed with percutaneous biopsy tissue: A case report

Xi¹,

Huang²,

Xi³

et al. 2020

WJCC

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“…Imatinib is a selective RTK inhibitor that binds the kinase domain of c-KIT. Inhibition of c-KIT-mutant melanoma with imatinib has produced objective response rate of 24.4% and disease control rate of 66.7% in patients with mutations in exons 11 (L576P) and 13 (K642E) [ 21 ]. In comparison, treatment of c-KIT-mutant GIST with imatinib yielded a response rate of 80%, with over 90% of patients remaining progression free at one year [ 22 , 135 ].…”

Section: C-kitmentioning

confidence: 99%

“…Diminished clinical efficacy of imatinib therapy in c-KIT mutant melanoma may be a result of secondary acquired resistance caused by higher genetic mutation load, presence of activating or secondary c-KIT mutations, re-activation of redundant downstream survival signaling pathways, and/or tumor microenvironment cytokines [ 140 , 141 , 142 , 143 , 144 ]. 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 ].…”

Section: C-kitmentioning

confidence: 99%

“…The average somatic mutation rate of c-KIT-mutant melanomas is even higher (30 mutations per Mb, n = 3, p = 0.02) compared to severely sun-damaged (SSD) skin (21 per Mb) and non-SSD skin (3.8 per Mb) [ 148 ]. Mutations in c-KIT have been found in up to 28% of melanomas on chronically sun-damaged skin, but not in non-acral melanomas, unrelated to chronically sun-damaged skin [ 21 ]. In some cases of melanoma, resistance to targeted therapy appears to be related to the acquisition of new mutations in other genes that contribute to tumor growth.…”

Section: C-kitmentioning

confidence: 99%

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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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“…Among the multiple genes affected by alterations that could potentially lead to melanoma development, mutations in c-KIT are becoming an appealing target for personalized therapy. This proto-oncogene encodes for a receptor tyrosine kinase (RTK), and its mutations were found in other cancer types [ 34 ]. Although alterations in KIT were identified in only 3% of all melanomas, they were frequently (28–39%) detected in melanoma arising from CSD skin, acral and mucosal sites [ 35 , 36 ].…”

Section: Biomarkers In Target Therapymentioning

confidence: 99%

Molecular and Immune Biomarkers for Cutaneous Melanoma: Current Status and Future Prospects

Pilla

Alberti

Mauro

et al. 2020

Cancers

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Advances in the genomic, molecular and immunological make-up of melanoma allowed the development of novel targeted therapy and of immunotherapy, leading to changes in the paradigm of therapeutic interventions and improvement of patients’ overall survival. Nevertheless, the mechanisms regulating either the responsiveness or the resistance of melanoma patients to therapies are still mostly unknown. The development of either the combinations or of the sequential treatment of different agents has been investigated but without a strongly molecularly motivated rationale. The need for robust biomarkers to predict patients’ responsiveness to defined therapies and for their stratification is still unmet. Progress in immunological assays and genomic techniques as long as improvement in designing and performing studies monitoring the expression of these markers along with the evolution of the disease allowed to identify candidate biomarkers. However, none of them achieved a definitive role in predicting patients’ clinical outcomes. Along this line, the cross-talk of melanoma cells with tumor microenvironment plays an important role in the evolution of the disease and needs to be considered in light of the role of predictive biomarkers. The overview of the relationship between the molecular basis of melanoma and targeted therapies is provided in this review, highlighting the benefit for clinical responses and the limitations. Moreover, the role of different candidate biomarkers is described together with the technical approaches for their identification. The provided evidence shows that progress has been achieved in understanding the molecular basis of melanoma and in designing advanced therapeutic strategies. Nevertheless, the molecular determinants of melanoma and their role as biomarkers predicting patients’ responsiveness to therapies warrant further investigation with the vision of developing more effective precision medicine.

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KIT and Melanoma: Biological Insights and Clinical Implications

Cited by 74 publications

References 91 publications

Primary pulmonary malignant melanoma diagnosed with percutaneous biopsy tissue: A case report

Primary pulmonary malignant melanoma diagnosed with percutaneous biopsy tissue: A case report

Resistance to Molecularly Targeted Therapies in Melanoma

Molecular and Immune Biomarkers for Cutaneous Melanoma: Current Status and Future Prospects

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