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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer

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Autor(es):
Gomes-Filho, Sandro Mascena [1] ; dos Santos, Edmilson Ozorio [2] ; Matos Bertoldi, Ester Riserio [1] ; Scalabrini, Luiza Coimbra [1] ; Heidrich, Vitor [1] ; Dazzani, Bianca [1] ; Levantini, Elena [3, 4] ; Reis, Eduardo Moraes [1] ; Basseres, Daniela Sanchez [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Av Prof Lineu Prestes 748, Bloco 12 Inferior, BR-05508000 Sao Paulo, SP - Brazil
[2] Inst Butantan, Sao Paulo, SP - Brazil
[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02115 - USA
[4] Natl Res Council CNR, Inst Biomed Technol, Pisa - Italy
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: CELLULAR ONCOLOGY; v. 43, n. 3 MAR 2020.
Citações Web of Science: 0
Resumo

Purpose Oncogenic KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs). As yet, however, no effective therapies are available for KRAS-induced malignancies. Therefore, research aimed at the identification of KRAS targets with therapeutic potential is warranted. Our goal was to investigate Aurora A (AURKA) and targeting protein for Xklp2 (TPX2) as potential therapeutic targets in PDAC. Methods AURKA and TPX2 expression was assessed using RNAseq and qRT-PCR in PDAC patient samples and matched non-tumor pancreatic tissues. Publicly available PDAC datasets were used to investigate associations of AURKA and TPX2 expression levels with patient survival and the presence of KRAS mutations. Next, we used an Aurora kinase inhibitor, or KRAS, AURKA and TPX2 targeting using RNA interference in KRAS-mutant PDAC cells and, subsequently, analyzed their clonogenic and anchorage-independent growth and migration. Results We found that relative to matched non-tumor tissues, PDAC tumors displayed significantly higher expression levels of AURKA and TPX2. In addition, we found that AURKA and TPX2 were co-expressed in PDAC datasets, and that high expression levels of AURKA and TPX2 were associated with a shorter patient survival and with the presence of oncogenic KRAS mutations. In addition, we found that siRNA-mediated KRAS targeting in KRAS-mutant PDAC cells reduced AURKA and TPX2 expression. Furthermore, targeting AURKA or TPX2 in KRAS-mutant PDAC cells reduced their clonogenic and anchorage-independent growth, as well their migration. Conclusions From our data we conclude that AURKA and TPX2 may act as KRAS biomarkers in PDAC that can predict a worse prognosis, and that AURKA or TPX2 targeting in PDAC cells may reduce their transformed phenotype. These results indicate that AURKA and TPX2 may serve as promising targets to be explored for KRAS-mutant PDAC therapy. (AU)

Processo FAPESP: 16/19757-2 - EXPLORANDO A QUINASE IKKbeta COMO UM ALVO TERAPÊUTICO ANTI-METASTÁTICO NO CÂNCER DE PULMÃO INDUZIDO PELO ONCOGENE KRAS
Beneficiário:Daniela Sanchez Basseres
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 10/52685-9 - Novos alvos terapêuticos no câncer de pulmão associado a mutações no oncogênese K-Ras
Beneficiário:Daniela Sanchez Basseres
Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores