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

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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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Acknowledgements

This work was supported by a Young Investigator Grant (2010/52685-9) and a Research Grant (2016/19757-2) from the Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP) to D.S.B., an Established Researcher fellowship (308663/2018-7) to E.M.R. by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), CNPq Ph.D. fellowships to E.O.S. (166803/2013-8) and L.C.S. (155381/2016-4) and by an undergraduate CNPq fellowship to V.H (PIBIC 2017/701). This work was also supported by a Ph.D. fellowhip to S.M.G-F. by the graduate program in Biochemistry and Molecular Biology of the University of São Paulo, which is sponsored by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, PROEX 1888/2016).

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  1. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil

    Sandro Mascena Gomes-Filho, Ester Risério Matos Bertoldi, Luiza Coimbra Scalabrini, Vitor Heidrich, Bianca Dazzani, Eduardo Moraes Reis & Daniela Sanchez Bassères

  2. Instituto Butantã, São Paulo, SP, Brazil

    Edmilson Ozorio dos Santos

  3. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Elena Levantini

  4. Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy

    Elena Levantini

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  1. Sandro Mascena Gomes-Filho
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The study involving human samples was approved by the Ethics Committee of the AC Camargo Cancer Center (CAAE: 15059213.0.0000.5432). All procedures used were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Gomes-Filho, S.M., dos Santos, E.O., Bertoldi, E.R.M. et al. Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer. Cell Oncol. 43, 445–460 (2020). https://doi.org/10.1007/s13402-020-00498-5

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