RTK Inhibitors in Melanoma: From Bench to Bedside

Sabbah, Malak; Najem, Ahmad; Krayem, Mohammad; Awada, Ahmad; Journé, Fabrice; Ghanem, Ghanem Elias

doi:10.3390/cancers13071685

Cited by 29 publications

(28 citation statements)

References 223 publications

(270 reference statements)

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“…The present study used B16BL6 and MEWO cells. Other studies have reported that B16 cell lines express wild-type B-Raf, and offer a model system for studying alternative mechanisms that give rise to malignant melanoma (43)(44)(45)(46). MeWo cells were also reported to express c-Kit (47).…”

Section: Discussionmentioning

confidence: 98%

Sorafenib treatment of metastatic melanoma with c‑Kit aberration reduces tumor growth and promotes survival

et al. 2021

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Melanomas are highly malignant tumors that readily metastasize and have poor prognosis. Targeted therapy is a cornerstone of treatment for patients with melanoma. Although c-Kit gene aberration has found in 5-10% of melanoma cases, research on c-Kit inhibitors for melanoma with c-Kit aberration have been disappointing. Sorafenib is a tyrosine kinase inhibitor, whose targets include c-Kit, platelet derived growth factor receptor (PDGFR), VEGFR and RAF. The present study aimed to examine the effect of sorafenib on metastatic melanoma with c-Kit aberration. Cell viability was assessed via trypan blue assay. Migration and invasion were analyzed using cell culture inserts. The anti-metastatic effects and antitumour activity of sorafenib were determined in an in vivo model. Protein expression was detected via western blotting, and the expression of MMP and very late antigen (VLA) was detected via reverse transcription-quantitative PCR. It was identified that sorafenib decreased cell viability, migration and invasion in vitro. Furthermore, sorafenib inhibited metastasis and tumor growth in vivo. Mechanistically, sorafenib inhibited c-Kit, PDGFR, VEGFR, B-Raf and c-Raf phosphorylation both in vitro and in vivo. In addition, sorafenib reduced the expression levels of MMPs and VLA. Importantly, there was a significant effect of sorafenib treatment on overall survival in mice. Collectively, this study suggests that sorafenib may serve as a novel therapeutic option for melanoma with c-Kit dysregulation.Cells and culture conditions. Murine melanoma cell lines, B16F1 and B16BL6, were kindly provided by Dr Inufusa of Kindai University (Osaka, Japan). B16F1 cells were established from lung metastasis lesions from the intravenous injection of

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Section: Discussionmentioning

confidence: 98%

Sorafenib treatment of metastatic melanoma with c‑Kit aberration reduces tumor growth and promotes survival

et al. 2021

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“…There are already several different drugs that are available for the extraocular melanomas, such as BRAF inhibitors and c-KIT inhibitors, and it is possible repurpose them to treat CM [45][46][47]. These therapies are helping the management of melanomas, but they do not always induce remission.…”

Section: Discussionmentioning

confidence: 99%

Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma

Djulbegovic

Uversky

Harbour

et al. 2021

Genes

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In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR®) and the Search Tool for the Retrieval of Interacting Genes (STRING®). Our PONDR® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected (p-value < 1.0 × 10−16). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM.

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“…Dubermatinib is another selective AXL inhibitor that was investigated in CLL (NCT03572634) and solid tumors (NCT02729298). Other non-selective AXL inhibitors that have the latter among their targets, such as crizotinib, bosutinib, and cabozantinib, and multi-targeted TKI, such as sunitinib, foretinib, and sitravatinib, are also available in clinics [ 126 ].…”

Section: Targeting Phenotypic Plasticity: Identifying New Vulnerabili...mentioning

confidence: 99%

Understanding Molecular Mechanisms of Phenotype Switching and Crosstalk with TME to Reveal New Vulnerabilities of Melanoma

Najem

Soumoy

Sabbah

et al. 2022

Cells

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Melanoma cells are notorious for their high plasticity and ability to switch back and forth between various melanoma cell states, enabling the adaptation to sub-optimal conditions and therapeutics. This phenotypic plasticity, which has gained more attention in cancer research, is proposed as a new paradigm for melanoma progression. In this review, we provide a detailed and deep comprehensive recapitulation of the complex spectrum of phenotype switching in melanoma, the key regulator factors, the various and new melanoma states, and corresponding signatures. We also present an extensive description of the role of epigenetic modifications (chromatin remodeling, methylation, and activities of long non-coding RNAs/miRNAs) and metabolic rewiring in the dynamic switch. Furthermore, we elucidate the main role of the crosstalk between the tumor microenvironment (TME) and oxidative stress in the regulation of the phenotype switching. Finally, we discuss in detail several rational therapeutic approaches, such as exploiting phenotype-specific and metabolic vulnerabilities and targeting components and signals of the TME, to improve the response of melanoma patients to treatments.

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RTK Inhibitors in Melanoma: From Bench to Bedside

Cited by 29 publications

References 223 publications

Sorafenib treatment of metastatic melanoma with c‑Kit aberration reduces tumor growth and promotes survival

Sorafenib treatment of metastatic melanoma with c‑Kit aberration reduces tumor growth and promotes survival

Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma

Understanding Molecular Mechanisms of Phenotype Switching and Crosstalk with TME to Reveal New Vulnerabilities of Melanoma

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