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.

Data documento
06/05/2024

Título
Genomic profile of two Brazilian choroid plexus tumors by whole-exome sequencing

Autor(es)
Garcia F.A.O. - Evangelista A.F. - Mançano B.M. - Moreno D.A. - Berardinelli G.N. - de Paula F.E. - Antoniazzi A.P. - Júnior C.A. - Lombardi I. - Santana I. - Teixeira G.R. - Costa C.E. - Reis R.M.

Palavras chave
neoplasm of the nervous system

Resumo
Choroid plexus tumors (CPTs) are rare intracranial neoplasms, representing <1% of all brain tumors, yet they represent 20% of first-year pediatric brain tumors. Although these tumors have been linked to TP53 germline mutations in the context of Li-Fraumeni syndrome, their somatic driver alterations remain poorly understood. In this study, we report two cases of lateral ventricle tumors: 3-yr-old male diagnosed with an atypical choroid plexus papilloma (aCPP), and a 6-mo-old female diagnosed with a choroid plexus carcinoma (CPC). We performed whole-exome sequencing of paired blood and tumor tissue in both patients, categorized somatic variants, and determined copy-number alterations. Our analysis revealed a tier II variant (Association for Molecular Pathology [AMP] criteria) in BRD1, a H3 and TP53 acetylation agent, in the aCPP. In addition, we detected copy-number gains on Chromosomes 12, 18, and 20 and copy-number losses on Chromosomes 13q and 22q (BRD1 locus) in this tumor. The CPC tumor had only a pathogenic germline TP53 variant, based on American College of Medical Genetics (ACMG) criteria, with a clinical and familiar history of Li-Fraumeni syndrome. The CPC patient presented loss of heterozygosity (LoH) of TP53 loci and hyperdiploid genome. Both tumors were microsatellite-stable. This is the first study performing whole-exome sequencing in Brazilian choroid plexus tumors, and in line with the literature, we corroborate the absence of recurrent somatic mutations in these tumors. Further studies with larger sample sizes are necessary to confirm our findings and better understand the underlying biology of these tumors.

Citação
Garcia FAO, Evangelista AF, Mançano BM, Moreno DA, Berardinelli GN, de Paula FE, Antoniazzi AP, Júnior CA, Lombardi I, Santana I, Teixeira GR, Costa CE, Reis RM. Genomic profile of two Brazilian choroid plexus tumors by whole-exome sequencing. Cold Spring Harb Mol Case Stud. 2023 Mar 24;9(1):a006245. doi: 10.1101/mcs.a006245. PMID: 36963804; PMCID: PMC10111795.