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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: CELLULAR ONCOLOGY; v. 43, n. 3 MAR 2020.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 16/19757-2 - EXPLORING IKKbeta KINASE AS AN ANTI-METASTATIC THERAPEUTIC TARGET IN KRAS-INDUCED LUNG CANCER
• Grantee: Daniela Sanchez Basseres
• Support Opportunities: Regular Research Grants