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Role of the HGF/c-MET tyrosine kinase inhibitors in metastasic melanoma.

ABSTRACT: Metastatic disease in a cancer patient still remains a therapeutic challenge. Metastatic process involves many steps, during which malignant cells succeed to activate cellular pathways promoting survival in hostile environment, engraftment and growth at the distant site from the primary tumor. Melanoma is known for its high propensity to produce metastases even at the early stages of the disease. Here we summarize the most important molecular mechanisms which were associated with the melanoma metastasis. Then, we specifically focus on the signaling pathway mediated by hepatocyte growth factor (HGF) and its receptor c-Met, which play an important role during physiological processes and were been associated with tumorigenesis. We also focus on the effect of the small molecule inhibitors of the tyrosine kinase domain of the c-Met receptor and its effects on properties of melanoma cell. We summarize recent studies, which involved inhibition of the HGF/c-Met signaling in order to decrease melanoma growth and metastatic capacity.

SUBMITTER: Demkova L

PROVIDER: S-EPMC5817811 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Role of the HGF/c-MET tyrosine kinase inhibitors in metastasic melanoma.

Demkova Lucia L Kucerova Lucia L

Molecular cancer 20180219 1

Metastatic disease in a cancer patient still remains a therapeutic challenge. Metastatic process involves many steps, during which malignant cells succeed to activate cellular pathways promoting survival in hostile environment, engraftment and growth at the distant site from the primary tumor. Melanoma is known for its high propensity to produce metastases even at the early stages of the disease. Here we summarize the most important molecular mechanisms which were associated with the melanoma me ...[more]

PMID: 29455657

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Project description:BackgroundThe Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies.MethodsEighty-six NSCLC patients were categorized into three cohorts based on the time of detecting MET tyrosine kinase domain (TKD) mutations (cohort 1: at baseline; cohort 2: after MET-TKI treatment; cohort 3: after EGFR-TKI treatment). Baseline and paired TKI treatment samples were analyzed by targeted next-generation sequencing.ResultsMET TKD mutations were highly prevalent in METex14-positive NSCLC patients after MET-TKI treatment, including L1195V, D1228N/H/Y/E, Y1230C/H/N/S, and a double-mutant within codons D1228 and M1229. Missense mutations in MET TKD were also identified at baseline and in post-EGFR-TKI treatment samples, which showed different distribution patterns than those in post-MET-TKI treatment samples. Remarkably, H1094Y and L1195F, absent from MET-TKI-treated patients, were the predominant type of MET TKD mutations in patients after EGFR-TKI treatment. D1228H, which was not found in treatment-naïve patients, also accounted for 14.3% of all MET TKD mutations in EGFR-TKI-treated samples. Two patients with baseline EGFR-sensitizing mutations who acquired MET-V1092I or MET-H1094Y after first-line EGFR-TKI treatment experienced an overall improvement in their clinical symptoms, followed by targeted therapy with MET-TKIs.ConclusionsMET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

Dataset Information

Role of the HGF/c-MET tyrosine kinase inhibitors in metastasic melanoma.

Publications

Role of the HGF/c-MET tyrosine kinase inhibitors in metastasic melanoma.

Similar Datasets

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