Transcription factors as critical players in melanoma invasiveness, drug resistance, and opportunities for therapeutic drug development

Cohen‐Solal, Karine; Kaufman, Howard L.; Lasfar, Ahmed

doi:10.1111/pcmr.12666

Cited by 25 publications

(20 citation statements)

References 76 publications

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“…It is in line with the current view that in parallel to genetic alterations, melanoma cell-autonomous mechanisms of resistance can rely on complex transcriptomic adaptations supported by epigenetic regulations, including miRNA-mediated mechanisms, and extended by the interplay between tumor and stromal cells that involves cell-cell interactions, paracrine stimulation and extracellular vesicles to create a resistance-permissive niche [39][40][41][42][43][44][45][46]. Mechanisms of resistance primarily directed to support proliferation and survival of cancer cells implicate a plethora of transcriptional regulators, adaptive responses, and feedback loops that extensively affect melanoma cell phenotype enabling the expansion of distinct cell subpopulations in the presence of drug(s) [27,[47][48][49][50][51][52]. Several evidence indicates that a multicellular heterogenous ecosystem of melanoma is changed in a stepwise manner during development of resistance, and many alterations accompanying this process are reversible in nature, which contributes to a high phenotypic plasticity of melanoma cells [16,36,[53][54][55][56][57].…”

Section: Discussionmentioning

confidence: 99%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line-and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKT high resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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“…Since melanoma derives from melanocytes that originate from precursor cells in the neural crest 7,8 , melanoma cells share some stem cell-like phenotypes with neural crest cells and express similar transcription factors that lead to those phenotypes 8 . The roles of these transcription factors, especially microphthalmia-associated transcription factor (MITF) and SRY (sex determining region Y)-Box (SOX) family 9 , in the resistance of melanoma to targeted treatments have been investigated by some previous studies. In melanoma cells resistant to MAPK inhibitors including BRAFi, a state of low expressions of MITF and SOX10 could induce high levels of tyrosine kinase receptors, such as AXL receptor tyrosine kinase (AXL) and epidermal growth factor receptor (EGFR) that help to maintain the resistance 10,11 .…”

Section: Introductionmentioning

confidence: 99%

POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation

Liu

Qiao

et al. 2020

Cell Death Dis

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BRAF inhibitors (BRAFi) have shown remarkable clinical efficacy in the treatment of melanoma with BRAF mutation. Nevertheless, most patients end up with the development of BRAFi resistance, which strongly limits the clinical application of these agents. POU4F1 is a stem cell-associated transcriptional factor that is highly expressed in melanoma cells and contributes to BRAF-activated malignant transformation. However, whether POU4F1 contributes to the resistance of melanoma to BRAFi remains poorly understood. Here, we report that over-expressed POU4F1 contributed to the acquired resistance of melanoma cells to Vemurafenib. Furthermore, POU4F1 promoted the activation of ERK signaling pathway via transcriptional regulation on MEK expression. In addition, POU4F1 could increase the expression of MITF to retain the resistance of melanoma cells to BRAFi. Collectively, our findings reveal that POU4F1 reactivates the MAPK pathway by transcriptional regulation on MEK expression and promotes MITF expression, which ultimately results in the resistance to BRAFi in melanoma. Our study supports that POU4F1 is a potential combined therapeutic target with BRAFi therapy for melanoma.

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“…Despite the improvement in diagnosis and clinical therapy (4)(5)(6)(7)(8), there is still a high mortality rate among melanoma patients (9)(10)(11). In addition, melanoma cells develop drug resistance to clinical treatments and survival (12)(13)(14). Hence, there is an urgent need to identify novel drugs and strategies to improve melanoma treatment (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

RNAi-mediated IARS2 knockdown inhibits proliferation and promotes apoptosis in human melanoma A375 cells

Song

Chen

et al. 2020

Oncol Lett

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IARS2, which encodes the mitochondrial form of isoleucyl-tRNA synthetase, has been found to play an important role in a range of diseases, including cancer. However, the relationship between IARS2 and melanoma is still unclear. To evaluate the role of IARS2 in melanoma, we constructed a stable A375 cell line with IARS2 knockdown via lentivirus-mediated small interfering RNAs. The expression of IARS2 was measured by real time-quantitative Polymerase Chain Reaction and western blot analysis. Cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and colony formation assay were conducted to assess the effect of IARS2 on melanoma cell proliferation. Flow cytometry assay was used to determine cell apoptosis and cell cycle distribution in melanoma A375 cells. Finally, immunohistochemistry was employed to validate the expression of IARS2 protein in melanoma tissues. In this study it was found that IARS2 was highly expressed in melanoma cell lines. Furthermore, IARS2 protein also exhibited elevated expression in the tumour tissues obtained from melanoma patients. After suppression of the mRNA expression of IARS2, the proliferation and colony formation ability of the A375 cells were significantly inhibited, while the proportion of apoptotic A375 cells increased significantly, as indicated by an enhanced phosphatidylserine externalization and caspase 3/7 activity after IARS2 knockdown. Further investigations found that knockdown of IARS2 arrested cells in the G1 phase. The results suggested that IARS2 is critical for proliferation and apoptosis of melanoma cells.

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Transcription factors as critical players in melanoma invasiveness, drug resistance, and opportunities for therapeutic drug development

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Cited by 25 publications

References 76 publications

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation

RNAi-mediated IARS2 knockdown inhibits proliferation and promotes apoptosis in human melanoma A375 cells

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