Husna, Amity University Kolkata
What is a BRAF inhibitor and what is its role?
BRAF is a gene that is present on chromosome 7q34. It encodes a protein that has the ability to regulate the MAP kinase/ERKs-signaling pathway. These pathways have a crucial role in regulating cell division, differentiation, and the growth and proliferation of cells. Any oncogenic mutation can activate this gene and lead to the development of melanoma cancer. However, the BRAF inhibitors (vemurafenib and dabrafenib) play a very important role in the treatment of patients with BRAF-mutant melanoma cancer. They do so by interfering with the mitogen-activated protein kinase (MAPK) signalling pathway due to which the proliferation and survival of melanoma are regulated. Hence, small molecules of BRAF mutant inhibitors (BRAFi) were designed specifically to target the MAP kinase (MAPK) signalling pathway.
BRAF inhibitors (BRAFi) resistance:
BRAF inhibitors (BRAFi) have a great potential for treating -melanoma, giving a remarkable response, and increased overall survival rates. However, it has shortcomings as well. The clinical benefit of BRAF inhibitors is hindered as they acquire resistance. There are many routes that help BRAFi to acquire resistance. BRAF allele amplification or splice variants, reactivation of the MAPK pathway, and substitutive pathways are the routes.
Recent Study:
According to several studies, an interesting phenomenon has been revealed. Discontinued drug treatment in the resistant melanoma cells have resulted in massive cell mortality, i.e., interestingly, the resistant cells get addicted to the same drugs which were used for eliminating them. So, upon the withdrawal of drugs, these BRAFi-addicted melanoma cells experience a temporary slowdown in their cell cycle, and eventually, it leads to cell death.
This phenotype prompted ERK reactivation, which in turn, upregulated p38-FRA1-JUNB-CDKN1A expression, as well as, slowed down proliferation. In addition, ERK2 was revealed to act as a “switch” in cancer drug addiction, this is because the genetic inactivation of ERK2 could reverse the drug withdrawal-induced cell death in melanoma.
Proteomic and Phosphoproteomic study of BRAFi-addicted melanoma cells:
In ERK2-dependent drug addiction, various transcription factors like JUNB, FRA1, and MITF have a very important role to play. They can reprogram the ERK2-JUNBFRA1-MITF pathway.
It was very crucial to study the proteome and phosphoproteome of BRAFi addicted melanoma cells (i.e., 451Lu cell line) in response to BRAFi withdrawal and show them systematically.
To understand the function of ERK1, ERK2, and JUNB in response to drug withdrawal, researchers silenced these genes BRAFi-addicted melanoma cells by CRISPR-Cas9 and displayed a systematic proteomic and phosphoproteomic profiling.
Conclusion and significance of the study:
- The proteomics and phosphoproteomics profiling of BRAFi-addicted melanoma cells (i.e., 451Lu cell line) were displayed in response to BRAFi withdrawal.
- Drug addiction was prevented and the drug withdrawal-induced cell death was reverted when the genes ERK2 and JUNB were silenced. However, ERK1 inactivation had no effect.
- Very similar proteomic profiles were displayed by depleted ERK2 and JUNB, upon the withdrawal of drugs.
- There was a strong increase in EMT-related proteins upon drug withdrawal in ERK1-depleted cells, which was nullified when ERK2 was silenced. So, according to these results, ERK2 silencing can affect EMT activation in drug-addicted melanoma cells upon drug withdrawal, but not ERK1.
Hence, the results of these studies show the crucial role of ERK1, ERK2, and JUNB in controlling the proteome response of drug-addicted melanoma cells upon withdrawal of drugs; this could help to build a future methodology for fighting drug resistance.
Also read: Understanding Epithelial-Mesenchymal Transition
References: Li, B., Kong, X., Post, H., Raaijmakers, L., Peeper, D. S., & Altelaar, M. (2021) Proteomics and phosphoproteomics profiling of drug-addicted brafi-resistant melanoma cells. Journal of Proteome Research, acs.jproteome.1c00331. https://doi.org/10.1021/acs.jproteome.1c00331
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