Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas

Vachtenheim, J; Ondrušová, Lubica

doi:10.3390/life11050424

Cited by 5 publications

(3 citation statements)

References 105 publications

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“…Despite advances in using a combination of drugs, the concept of targeting only the MAPK route remains questionable. As there are multiple mechanisms responsible for resistance to the inhibition of MAPK signaling in melanoma (56,57), alternative therapies should also be considered. Targeting HH and Bcl2 protein by the combination of GANT61 and obatoclax was effective in most melanoma cell lines tested previously (58).…”

Section: Discussionmentioning

confidence: 99%

The Hedgehog/GLI signaling pathway activates transcription of Slug (Snail2) in melanoma cells

et al. 2023

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In melanoma and other cancers, invasion, epithelialto-mesenchymal transition, metastasis and cancer stem cell maintenance are regulated by transcription factors including the Snail family. Slug (Snail2) protein generally supports migration and apoptosis resistance. However, its role in melanoma is not completely understood. The present study investigated the transcriptional regulation of the SLUG gene in melanoma. It demonstrated that SLUG is under the control of the Hedgehog/GLI signaling pathway and is activated predominantly by the transcription factor GLI2. The SLUG gene promoter contains a high number of GLI-binding sites. Slug expression is activated by GLI factors in reporter assays and inhibited by GANT61 (GLI inhibitor) and cyclopamine (SMO inhibitor). SLUG mRNA levels are lowered by GANT61 as assessed by reverse transcription-quantitative PCR. Chromatin immunoprecipitation revealed abundant binding of factors GLI1-3 in the four subregions of the proximal SLUG promoter. Notably, melanoma-associated transcription factor (MITF) is an imperfect activator of the SLUG promoter in reporter assays, and downregulation of MITF had no effect on endogenous Slug protein levels. Immunohistochemical analysis confirmed the above findings and showed MITF-negative regions in metastatic melanoma that were positive for GLI2 and Slug. Taken together, the results demonstrated a previously unrecognized transcriptional activation mechanism of the SLUG gene, which may represent its main regulation of expression in melanoma cells.

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Section: Discussionmentioning

confidence: 99%

The Hedgehog/GLI signaling pathway activates transcription of Slug (Snail2) in melanoma cells

et al. 2023

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“…Plasticity gives melanoma cells the ability to dynamically switch between a differentiated state with limited tumorigenic potential and an undifferentiated or cancer stem-like cell state (CSC) that is responsible for long-term tumor growth [81]. In addition to the ability to transit into distinct CSC states with different competence to evade drug toxicity to disseminate to distant organs, cancer cell plasticity has been shown to be linked to the epithelial-to-mesenchymal transition-like program in melanoma that relies not only on cell-autonomous mechanisms but also on signals provided by the tumor microenvironment and/or signals induced in response to therapy [82,83] in response to active mutations in key molecules of both MAPK and PI3K/AKT/PTEN pathways [84,85].…”

Section: Melanoma Heterogeneity and Plasticitymentioning

confidence: 99%

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells

Al Hmada,

Brodell,

Kharouf

et al. 2024

Cancers

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Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAFV600E). While the successful targeting of BRAFV600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.

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“…It has also been recently shown that NRAS mutations not only directly promote cell proliferation, but also block intracellular DNA damage [17][18][19] . Accordingly, NRAS mutations can lead to resistance of tumor cells to a variety of chemotherapeutic agents that damage intracellular DNA 20,21 .…”

mentioning

confidence: 99%

Dihydroartemisinin-driven selective anti-lung cancer proliferation by binding to EGFR and inhibition of NRAS signaling pathway-induced DNA damage

Li,

Peng,

Yang

et al. 2024

Sci Rep

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Chemotherapeutic agents can inhibit the proliferation of malignant cells due to their cytotoxicity, which is limited by collateral damage. Dihydroartemisinin (DHA), has a selective anti-cancer effect, whose target and mechanism remain uncovered. The present work aims to examine the selective inhibitory effect of DHA as well as the mechanisms involved. The findings revealed that the Lewis cell line (LLC) and A549 cell line (A549) had an extremely rapid proliferation rate compared with the 16HBE cell line (16HBE). LLC and A549 showed an increased expression of NRAS compared with 16HBE. Interestingly, DHA was found to inhibit the proliferation and facilitate the apoptosis of LLC and A549 with significant anti-cancer efficacy and down-regulation of NRAS. Results from molecular docking and cellular thermal shift assay revealed that DHA could bind to epidermal growth factor receptor (EGFR) molecules, attenuating the EGF binding and thus driving the suppressive effect. LLC and A549 also exhibited obvious DNA damage in response to DHA. Further results demonstrated that over-expression of NRAS abated DHA-induced blockage of NRAS. Moreover, not only the DNA damage was impaired, but the proliferation of lung cancer cells was also revitalized while NRAS was over-expression. Taken together, DHA could induce selective anti-lung cancer efficacy through binding to EGFR and thereby abolishing the NRAS signaling pathway, thus leading to DNA damage, which provides a novel theoretical basis for phytomedicine molecular therapy of malignant tumors.

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Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas

Cited by 5 publications

References 105 publications

The Hedgehog/GLI signaling pathway activates transcription of Slug (Snail2) in melanoma cells

The Hedgehog/GLI signaling pathway activates transcription of Slug (Snail2) in melanoma cells

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells

Dihydroartemisinin-driven selective anti-lung cancer proliferation by binding to EGFR and inhibition of NRAS signaling pathway-induced DNA damage

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