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Article

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

by
Martina Radić
1,†,‡,
Ignacija Vlašić
1,†,
Maja Jazvinšćak Jembrek
1,2,
Anđela Horvat
1,
Ana Tadijan
1,
Maja Sabol
3,
Marko Dužević
1,§,
Maja Herak Bosnar
1,* and
Neda Slade
1,*
1
Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
2
School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia
3
Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Current address: Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland.
§
Current address: In Vivo Pharmacology and Toxicology, Selvita Ltd., 10000 Zagreb, Croatia.
Int. J. Mol. Sci. 2022, 23(17), 9910; https://doi.org/10.3390/ijms23179910
Submission received: 20 July 2022 / Revised: 22 August 2022 / Accepted: 23 August 2022 / Published: 31 August 2022
(This article belongs to the Special Issue Molecular Biology of Melanoma 2.0)
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Abstract

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.
Keywords: melanoma; vemurafenib; drug resistance; signaling pathways; epithelial–mesenchymal transition (EMT); slow-cycling cells; NME metastasis suppressor proteins melanoma; vemurafenib; drug resistance; signaling pathways; epithelial–mesenchymal transition (EMT); slow-cycling cells; NME metastasis suppressor proteins

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MDPI and ACS Style

Radić, M.; Vlašić, I.; Jazvinšćak Jembrek, M.; Horvat, A.; Tadijan, A.; Sabol, M.; Dužević, M.; Herak Bosnar, M.; Slade, N. Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance. Int. J. Mol. Sci. 2022, 23, 9910. https://doi.org/10.3390/ijms23179910

AMA Style

Radić M, Vlašić I, Jazvinšćak Jembrek M, Horvat A, Tadijan A, Sabol M, Dužević M, Herak Bosnar M, Slade N. Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance. International Journal of Molecular Sciences. 2022; 23(17):9910. https://doi.org/10.3390/ijms23179910

Chicago/Turabian Style

Radić, Martina, Ignacija Vlašić, Maja Jazvinšćak Jembrek, Anđela Horvat, Ana Tadijan, Maja Sabol, Marko Dužević, Maja Herak Bosnar, and Neda Slade. 2022. "Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance" International Journal of Molecular Sciences 23, no. 17: 9910. https://doi.org/10.3390/ijms23179910

APA Style

Radić, M., Vlašić, I., Jazvinšćak Jembrek, M., Horvat, A., Tadijan, A., Sabol, M., Dužević, M., Herak Bosnar, M., & Slade, N. (2022). Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance. International Journal of Molecular Sciences, 23(17), 9910. https://doi.org/10.3390/ijms23179910

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