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Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance

Radić, Martina; Vlašić, Ignacija; Jazvinšćak Jembrek, Maja; Horvat, Anđela; Tadijan, Ana; Sabol, Maja; Dužević, Marko; Herak Bosnar, Maja; Slade, Neda (2022) Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance. International journal of molecular sciences, 23 (17). ISSN 1422-0067

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Regardless of the significant improvements in treatment of melanoma, the majority of patients develop resistance whose mechanisms are still not completely understood. Hence, we generated and characterized two melanoma-derived cell lines, primary WM793B and metastatic A375M, with acquired resistance to the RAF inhibitor vemurafenib. The morphology of the resistant primary WM793B melanoma cells showed EMT-like features and exhibited a hybrid phenotype with both epithelial and mesenchymal characteristics. Surprisingly, the vemurafenib-resistant melanoma cells showed a decreased migration ability but also displayed a tendency to collective migration. Signaling pathway analysis revealed the reactivation of MAPK and the activation of the PI3K/AKT pathway depending on the vemurafenib-resistant cell line. The acquired resistance to vemurafenib caused resistance to chemotherapy in primary WM793B melanoma cells. Furthermore, the cell-cycle analysis and altered levels of cell-cycle regulators revealed that resistant cells likely transiently enter into cell cycle arrest at the G0/G1 phase and gain slow-cycling cell features. A decreased level of NME1 and NME2 metastasis suppressor proteins were found in WM793B-resistant primary melanoma, which is possibly the result of vemurafenib-acquired resistance and is one of the causes of increased PI3K/AKT signaling. Further studies are needed to reveal the vemurafenib-dependent negative regulators of NME proteins, their role in PI3K/AKT signaling, and their influence on vemurafenib-resistant melanoma cell characteristics.

Item Type: Article
Uncontrolled Keywords: melanoma ; vemurafenib ; drug resistance ; signaling pathways ; epithelial–mesenchymal transition (EMT) ; slow-cycling cells ; NME metastasis suppressor proteins
Subjects: NATURAL SCIENCES > Biology
Divisions: Division of Molecular Medicine
Project titleProject leaderProject codeProject type
Otkrivanje novih proteinskih interakcija kao podloga za nove pristupe liječenju melanoma čovjekaSlade, NedaIP-2013-11-1615HRZZ
Depositing User: Maja Jazvinšćak Jembrek
Date Deposited: 19 Sep 2022 11:00
DOI: 10.3390/ijms23179910

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