Acquisition of resistance to vemurafenib leads to interleukin‐10 production through an aberrant activation of Akt in a melanoma cell line

Inozume, Takashi; Tsunoda, Toshiyuki; Morisaki, T.; Harada, Kazutoshi; Shirasawa, Seiji; Kawamura, Tatsuyoshi

doi:10.1111/1346-8138.14651

Cited by 5 publications

(3 citation statements)

References 18 publications

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“…A range of genetic mutations have been identified as causing acquired BRAF resistance (recently reviewed by Tian and Guo and summarized in Table 1 ) [ 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ...…”

Section: Resultsmentioning

confidence: 99%

“…In the tumor cell, this reversion to a low immunogenic state is caused by induced expression of programmed cell death ligand-1 (PD-L1) [ 165 , 166 , 167 , 168 , 169 ], increased expression of the immunoregulatory protein Galactin-1 [ 170 ], and increased expression of CD47, an immunoregulatory cell marker, on tumor cells, leading to reduced killing by cytotoxic T-cells and macrophages [ 133 ]. BRAF inhibitor-resistant tumor cells also show reduced expression of target antigens [ 164 ], and increased production of IL-10 [ 33 ]. They also show upregulation of the IGF receptor, which sensitizes BRAF inhibitor-resistant cells to the effects of cytotoxic T-lymphocytes by increasing the cellular uptake of granzyme B [ 171 ].…”

Section: Resultsmentioning

confidence: 99%

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Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Proietti

Skroza

Bernardini

et al. 2020

Cancers

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This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Proietti

Skroza

Bernardini

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…As compared with parental cells, both vemurafenib-resistant cell clones showed increased secretion of IL-10, considered an important autocrine growth factor for malignant melanoma [32] and found to be upregulated in vemurafenib-resistant cells [33] of VEGF, a potent angiogenic factor also involved in BRAFi-resistance of melanoma cells [34], and of IL-1β and IL-8, cytokines that promote inflammation, tumorigenesis, and invasiveness [35]. Notably, increased expression of IL-8 has been found to be associated with multidrug resistance in breast cancer cells, sunitinib resistance in renal cell carcinoma, and RO4929097 (a γ-secretase inhibitor) resistance in NSCLC cells [36].…”

Section: Discussionmentioning

confidence: 96%

Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals

et al. 2021

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The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines—that potentially facilitate melanoma growth—than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-γ, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance.

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Elucidation of anti-human melanoma and anti-aging mechanisms of compounds from green seaweed Caulerpa racemosa

Wicaksono,

Taslim,

Lau

et al. 2024

Sci Rep

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Human melanoma is linked with aging-related disorders, prompting interest in the development of functional foods derived from natural ingredients to mitigate its incidence. Molecules in green seaweeds such as Caulerpa racemosa can serve this purpose due to their anti-tumor and anti-inflammatory properties. A previous work study compounds profiling has been carried out, and in this research the molecular docking studies targeting receptors associated with melanoma (GRP78, IRE1, BRAF) and aging (mTOR, AMPK, SIRT1) identified four promising compound in an extract of C. racemosa . The current study aims to the mechanism of those compounds at a cellular level using the human A375 (BRAF-V600E mutation) and A375 and B16-F10 cell lines. The MTT assay was used to evaluate the potential of GSCRE compounds against A375 and B16-F10 cell lines, with comparisons made to normal HDFa cell lines. Results indicated that compound C2, also known as Caulersin, demonstrated a significantly different ∆G affinity binding score compared to the control drug Dabrafenib. GSCRE crude extract, particularly C2, showed potential in modulating mTOR, AMPK, and SIRT1 pathways and downregulating GRP78, IRE1, and BRAF signaling ( p < 0.05). Interestingly, C2 was less effective in suppressing A375 and B16-F10 cell lines (LD 50 C2 < LD 50 Dabrafenib/control), with its LD 50 value nearly matching that of the Trametinib control in B16-F10 cell lines. Consequently, GSCRE, especially C2 or Caulersin, shows promise as a new molecule for developing functional foods to combat aging and human melanoma. However, further in vivo studies and clinical trials are necessary to confirm these findings. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-78464-6.

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Acquisition of resistance to vemurafenib leads to interleukin‐10 production through an aberrant activation of Akt in a melanoma cell line

Cited by 5 publications

References 18 publications

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals

Elucidation of anti-human melanoma and anti-aging mechanisms of compounds from green seaweed Caulerpa racemosa

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