Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines
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 inv...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/8/4409 |
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| author | Yixuan Ma Sina Sender Anett Sekora Weibo Kong Peter Bauer Najim Ameziane Susann Krake Mandy Radefeldt Ruslan Al-Ali Frank Ulrich Weiss Markus M. Lerch Alisha Parveen Dietmar Zechner Christian Junghanss Hugo Murua Escobar |
| author_facet | Yixuan Ma Sina Sender Anett Sekora Weibo Kong Peter Bauer Najim Ameziane Susann Krake Mandy Radefeldt Ruslan Al-Ali Frank Ulrich Weiss Markus M. Lerch Alisha Parveen Dietmar Zechner Christian Junghanss Hugo Murua Escobar |
| author_sort | Yixuan Ma |
| collection | DOAJ |
| description | 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 (<i>KRAS</i>) and tumor protein p53 (<i>TP53</i>), 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 <i>TP53</i> and <i>KRAS</i> affected the efficacy of both inhibitors. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T13:32:24Z |
| publishDate | 2022-04-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b183fc4e070c4ba7b11f82963a3586b62023-11-30T21:16:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01238440910.3390/ijms23084409Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell LinesYixuan Ma0Sina Sender1Anett Sekora2Weibo Kong3Peter Bauer4Najim Ameziane5Susann Krake6Mandy Radefeldt7Ruslan Al-Ali8Frank Ulrich Weiss9Markus M. Lerch10Alisha Parveen11Dietmar Zechner12Christian Junghanss13Hugo Murua Escobar14Department of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyCENTOGENE GmbH, 18057 Rostock, GermanyCENTOGENE GmbH, 18057 Rostock, GermanyCENTOGENE GmbH, 18057 Rostock, GermanyCENTOGENE GmbH, 18057 Rostock, GermanyDepartment of Medicine A, University Medicine, University of Greifswald, 17475 Greifswald, GermanyDepartment of Medicine A, University Medicine, University of Greifswald, 17475 Greifswald, GermanyInstitute for Experimental Surgery, University of Rostock, 18057 Rostock, GermanyInstitute for Experimental Surgery, University of Rostock, 18057 Rostock, GermanyDepartment of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyCasein 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 (<i>KRAS</i>) and tumor protein p53 (<i>TP53</i>), 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 <i>TP53</i> and <i>KRAS</i> affected the efficacy of both inhibitors.https://www.mdpi.com/1422-0067/23/8/4409casein kinase IIcyclin dependent kinasepancreatic ductal adenocarcinoma<i>KRAS</i><i>TP53</i> |
| spellingShingle | Yixuan Ma Sina Sender Anett Sekora Weibo Kong Peter Bauer Najim Ameziane Susann Krake Mandy Radefeldt Ruslan Al-Ali Frank Ulrich Weiss Markus M. Lerch Alisha Parveen Dietmar Zechner Christian Junghanss Hugo Murua Escobar Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines International Journal of Molecular Sciences casein kinase II cyclin dependent kinase pancreatic ductal adenocarcinoma <i>KRAS</i> <i>TP53</i> |
| title | Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines |
| title_full | Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines |
| title_fullStr | Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines |
| title_full_unstemmed | Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines |
| title_short | Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines |
| title_sort | inhibitory response to ck ii inhibitor silmitasertib and cdks inhibitor dinaciclib is related to genetic differences in pancreatic ductal adenocarcinoma cell lines |
| topic | casein kinase II cyclin dependent kinase pancreatic ductal adenocarcinoma <i>KRAS</i> <i>TP53</i> |
| url | https://www.mdpi.com/1422-0067/23/8/4409 |
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