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19.03.2020 | Original paper

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

verfasst von: Sandro Mascena Gomes-Filho, Edmilson Ozorio dos Santos, Ester Risério Matos Bertoldi, Luiza Coimbra Scalabrini, Vitor Heidrich, Bianca Dazzani, Elena Levantini, Eduardo Moraes Reis, Daniela Sanchez Bassères

Erschienen in: Cellular Oncology | Ausgabe 3/2020

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Abstract

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.

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Titel: Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer
verfasst von: Sandro Mascena Gomes-Filho
Edmilson Ozorio dos Santos
Ester Risério Matos Bertoldi
Luiza Coimbra Scalabrini
Vitor Heidrich
Bianca Dazzani
Elena Levantini
Eduardo Moraes Reis
Daniela Sanchez Bassères
Publikationsdatum: 19.03.2020
Verlag: Springer Netherlands
Erschienen in: Cellular Oncology / Ausgabe 3/2020
Print ISSN: 2211-3428
Elektronische ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-020-00498-5

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01.04.2024 | Forensische Traumatologie | CME

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

Abstract

Purpose

Methods

Results

Conclusions

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Conclusions

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