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Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines.
Ma, Yixuan; Sender, Sina; Sekora, Anett; Kong, Weibo; Bauer, Peter; Ameziane, Najim; Krake, Susann; Radefeldt, Mandy; Al-Ali, Ruslan; Weiss, Frank Ulrich; Lerch, Markus M; Parveen, Alisha; Zechner, Dietmar; Junghanss, Christian; Murua Escobar, Hugo.
Afiliação
  • Ma Y; Department of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany.
  • Sender S; Department of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany.
  • Sekora A; Department of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany.
  • Kong W; Department of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany.
  • Bauer P; Institute of Muscle Biology and Growth, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany.
  • Ameziane N; Department of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany.
  • Krake S; CENTOGENE GmbH, 18057 Rostock, Germany.
  • Radefeldt M; CENTOGENE GmbH, 18057 Rostock, Germany.
  • Al-Ali R; Arcensus GmbH, 18055 Rostock, Germany.
  • Weiss FU; CENTOGENE GmbH, 18057 Rostock, Germany.
  • Lerch MM; CENTOGENE GmbH, 18057 Rostock, Germany.
  • Parveen A; CENTOGENE GmbH, 18057 Rostock, Germany.
  • Zechner D; Department of Medicine A, University Medicine, University of Greifswald, 17475 Greifswald, Germany.
  • Junghanss C; Department of Medicine A, University Medicine, University of Greifswald, 17475 Greifswald, Germany.
  • Murua Escobar H; LMU Munich University Hospital, 81377 Munich, Germany.
Int J Mol Sci ; 23(8)2022 Apr 16.
Article em En | MEDLINE | ID: mdl-35457227
Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC cell lines exposed to increasing concentrations of silmitasertib and dinaciclib. Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated, and bioinformatic clustering was used to classify cell lines into sensitive groups based on their response to inhibitors. Furthermore, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) was conducted to assess recurrent mutations and the expression profile of inhibitor targets and genes frequently mutated in PDAC, respectively. Dinaciclib and silmitasertib demonstrated pronounced and limited cell line specific effects in cell death induction, respectively. WES revealed no genomic variants causing changes in the primary structure of the corresponding inhibitor target proteins. RNA-Seq demonstrated that the expression of all inhibitor target genes was higher in the PDAC cell lines compared to non-neoplastic pancreatic tissue. The observed differences in PDAC cell line sensitivity to silmitasertib or dinaciclib did not depend on target gene expression or the identified gene variants. For the PDAC hotspot genes kirsten rat sarcoma virus (KRAS) and tumor protein p53 (TP53), three and eight variants were identified, respectively. In conclusion, both inhibitors demonstrated in vitro efficacy on the PDAC cell lines. However, aberrations and expression of inhibitor target genes did not appear to affect the efficacy of the corresponding inhibitors. In addition, specific aberrations in TP53 and KRAS affected the efficacy of both inhibitors.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Limite: Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Limite: Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Suíça