Data documento
06/05/2024

Título
3-Bromopyruvate Suppresses the Malignant Phenotype of Vemurafenib-Resistant Melanoma Cells

Autor(es)
Vital P.D.S. - Bonatelli M, - Dias M.P. - de Salis L.V.V. - Pinto M.T. - Baltazar F. - Maria-Engler S.S. - Pinheiro C.

Palavras chave
drug resistance - melanoma - metabolism - proto-oncogene protein B-raf - vemurafenib

Resumo
(1) BRAF mutations are associated with high mortality and are a substantial factor in therapeutic decisions. Therapies targeting BRAF-mutated tumors, such as vemurafenib (PLX), have significantly improved the overall survival of melanoma patients. However, patient relapse and low response rates remain challenging, even with contemporary therapeutic alternatives. Highly proliferative tumors often rely on glycolysis to sustain their aggressive phenotype. 3-bromopyruvate (3BP) is a promising glycolysis inhibitor reported to mitigate resistance in tumors. This study aimed to evaluate the potential of 3BP as an antineoplastic agent for PLX-resistant melanoma treatment. (2) The effect of 3BP alone or in combination with PLX on viability, proliferation, colony formation, cell death, migration, invasion, epithelial-mesenchymal marker and metabolic protein expression, extracellular glucose and lactate, and reactive species were evaluated in two PLX-resistant melanoma cell lines. (3) 3BP treatment, which was more effective as monotherapy than combined with PLX, disturbed the metabolic and epithelial-mesenchymal profile of PLX-resistant cells, impairing their proliferation, migration, and invasion and triggering cell death. (4) 3BP monotherapy is a potent metabolic-disrupting agent against PLX-resistant melanomas, supporting the suppression of the malignant phenotype in this type of neoplasia.

Citação
Vital PDS, Bonatelli M, Dias MP, de Salis LVV, Pinto MT, Baltazar F, Maria-Engler SS, Pinheiro C. 3-Bromopyruvate Suppresses the Malignant Phenotype of Vemurafenib-Resistant Melanoma Cells. Int J Mol Sci. 2022 Dec 9;23(24):15650. doi: 10.3390/ijms232415650. PMID: 36555289; PMCID: PMC9779063.

Data documento
06/05/2024

Título
Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines

Autor(es)
Gomes I.N.F. - da Silva-Oliveira R.J. - da Silva L.S. - Martinho O. - Evangelista A.F. - van Helvoort Lengert A. - Leal L.F. - Silva V.A.O. - Dos Santos S.P. - Nascimento F.C. - Lopes Carvalho A. - Reis R.M.

Palavras chave
EGFR - biomarkers - cetuximab - drug resistance - head and neck tumors - in vitro - pre-clinical

Resumo
Cetuximab is the sole anti-EGFR monoclonal antibody that is FDA approved to treat head and neck squamous cell carcinoma (HNSCC). However, no predictive biomarkers of cetuximab response are known for HNSCC. Herein, we address the molecular mechanisms underlying cetuximab resistance in an in vitro model. We established a cetuximab resistant model (FaDu), using increased cetuximab concentrations for more than eight months. The resistance and parental cells were evaluated for cell viability and functional assays. Protein expression was analyzed by Western blot and human cell surface panel by lyoplate. The mutational profile and copy number alterations (CNA) were analyzed using whole-exome sequencing (WES) and the NanoString platform. FaDu resistant clones exhibited at least two-fold higher IC50 compared to the parental cell line. WES showed relevant mutations in several cancer-related genes, and the comparative mRNA expression analysis showed 36 differentially expressed genes associated with EGFR tyrosine kinase inhibitors resistance, RAS, MAPK, and mTOR signaling. Importantly, we observed that overexpression of KRAS, RhoA, and CD44 was associated with cetuximab resistance. Protein analysis revealed EGFR phosphorylation inhibition and mTOR increase in resistant cells. Moreover, the resistant cell line demonstrated an aggressive phenotype with a significant increase in adhesion, the number of colonies, and migration rates. Overall, we identified several molecular alterations in the cetuximab resistant cell line that may constitute novel biomarkers of cetuximab response such as mTOR and RhoA overexpression. These findings indicate new strategies to overcome anti-EGFR resistance in HNSCC.

Citação
Gomes INF, da Silva-Oliveira RJ, da Silva LS, Martinho O, Evangelista AF, van Helvoort Lengert A, Leal LF, Silva VAO, Dos Santos SP, Nascimento FC, Lopes Carvalho A, Reis RM. Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines. Cells. 2022 Jan 4;11(1):154. doi: 10.3390/cells11010154. PMID: 35011716; PMCID: PMC8750399.