engleski

Unique Hallmarks of Targeted Therapy Resistant Melanoma Cell Lines

Melanoma is skin cancer developed from melanocytes and is considered to be one of the most aggressive tumor types due to high metastatic potential. One of the reasons why melanoma is prone to metastasis is a process known as a phenotype switching which is similar to epithelial–mesenchymal transition (EMT) since it includes EMT-related genes and signaling pathways. In addition, this process is shown to be implicated in resistance to targeted therapy. Depending on the BRAF mutation status, first line treatment options for melanoma can include targeted therapy or immunotherapy for BRAF-mutated melanoma, or immunotherapy for wild- type BRAF melanoma. Around 60% of melanoma carry BRAF mutation, of which almost 90% harbor BRAF V600E mutation that causes continuous activation of the MAPK signaling pathway. BRAF V600E mutated kinase can be targeted by BRAF inhibitor (BRAFi), vemurafenib, which is a first targeted therapy licensed for treatment of advanced melanoma. Although initial response in the clinic was very powerful, the disease relapses within several months of therapy introduction due to occurrence of acquired resistance to BRAFi therapy. Reactivation of the MAPK pathway occurs in the majority of BRAFi-resistant tumors, while the second most frequently activated signaling pathway is PI3K/AKT. So to investigate the underlying molecular mechanisms of BRAFi targeted therapy resistance in more detail, we generated and characterized two melanoma cell lines with acquired resistance to vemurafenib. The resistant cell lines exhibited specific features of slow cycling cells possibly as a consequence of vemurafenib-driven phenotype switching. These characteristics included morphological and molecular features of EMT-like cells, enhanced resistance to chemotherapy, changed levels of cell-cycle regulators and thus reduced proliferation. Additional features included decreased migration ability but tendency toward collective migration, and reactivation of MAPK or activation of PI3K/AKT signaling pathways, depending on the cell line. Reduced levels of NME1 and NME2 metastasis suppressor proteins were observed in primary vemurafenib-resistant cell line, which could originate from vemurafenib- acquired resistance and is one of the reasons for increased PI3K/AKT signaling. Further studies are required to reveal the vemurafenib-dependent suppressors of NME proteins, their association with PI3K/AKT signaling, and their impact on vemurafenib-resistant melanoma cell characteristics.

melanoma ; targeted therapy ; vemurafenib ; resistance ; phenotype switching ; slow cycling cells ; signaling pathways ; NME metastasis suppressor proteins

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