Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification
Abstract Background Cholangiocarcinoma is a rare but lethal cancer of the biliary tract. Its first-line treatment is currently restricted to chemotherapy, which provides limited clinical benefit. Kinase inhibitors targeting oncogenic intracellular signaling have changed the treatment paradigm of can...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-022-00498-1 |
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| author | Ruby Lieshout Alessandra V. S. Faria Maikel P. Peppelenbosch Luc J. W. van der Laan Monique M. A. Verstegen Gwenny M. Fuhler |
| author_facet | Ruby Lieshout Alessandra V. S. Faria Maikel P. Peppelenbosch Luc J. W. van der Laan Monique M. A. Verstegen Gwenny M. Fuhler |
| author_sort | Ruby Lieshout |
| collection | DOAJ |
| description | Abstract Background Cholangiocarcinoma is a rare but lethal cancer of the biliary tract. Its first-line treatment is currently restricted to chemotherapy, which provides limited clinical benefit. Kinase inhibitors targeting oncogenic intracellular signaling have changed the treatment paradigm of cancer over the last decades. However, they are yet to be widely applied in cholangiocarcinoma therapy. Cholangiocarcinoma has marked molecular heterogeneity, which complicates the discovery of new treatments and requires patient stratification. Therefore, we investigated whether a commercial kinome profiling platform could predict druggable targets in cholangiocarcinoma. Methods Kinase activity in patient-derived cholangiocarcinoma organoids, non-tumorous adjacent tissue-derived and healthy donor-derived intrahepatic cholangiocyte organoids was determined using the PamChip® phosphotyrosine kinase microarray platform. Kinome profiles were compared and correlated with RNA sequencing and (multi-)kinase inhibitor screening of the cholangiocarcinoma organoids. Results Kinase activity profiles of individual cholangiocarcinoma organoids are different and do not cluster together. However, growth factor signaling (EGFR, PDGFRβ) and downstream effectors (MAPK pathway) are more active in cholangiocarcinoma organoids and could provide potential druggable targets. Screening of 31 kinase inhibitors revealed several promising pan-effective inhibitors and compounds that show patient-specific efficacy. Kinase inhibitor sensitivity correlated to the activity of its target kinases for several inhibitors, signifying them as potential predictors of response. Moreover, we identified correlations between drug response and kinases not directly targeted by those drugs. Conclusions In conclusion, kinome profiling is a feasible method to identify druggable targets for cholangiocarcinoma. Future studies should confirm the potential of kinase activity profiles as biomarkers for patient stratification and precision medicine. |
| first_indexed | 2024-04-13T15:31:56Z |
| format | Article |
| id | doaj.art-383639e6c871433fabdfa2e494969105 |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-04-13T15:31:56Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-383639e6c871433fabdfa2e4949691052022-12-22T02:41:21ZengBMCMolecular Medicine1076-15511528-36582022-06-0128111510.1186/s10020-022-00498-1Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratificationRuby Lieshout0Alessandra V. S. Faria1Maikel P. Peppelenbosch2Luc J. W. van der Laan3Monique M. A. Verstegen4Gwenny M. Fuhler5Erasmus MC Transplant Institute, Department of Surgery, Erasmus University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus University Medical CenterErasmus MC Transplant Institute, Department of Surgery, Erasmus University Medical CenterErasmus MC Transplant Institute, Department of Surgery, Erasmus University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus University Medical CenterAbstract Background Cholangiocarcinoma is a rare but lethal cancer of the biliary tract. Its first-line treatment is currently restricted to chemotherapy, which provides limited clinical benefit. Kinase inhibitors targeting oncogenic intracellular signaling have changed the treatment paradigm of cancer over the last decades. However, they are yet to be widely applied in cholangiocarcinoma therapy. Cholangiocarcinoma has marked molecular heterogeneity, which complicates the discovery of new treatments and requires patient stratification. Therefore, we investigated whether a commercial kinome profiling platform could predict druggable targets in cholangiocarcinoma. Methods Kinase activity in patient-derived cholangiocarcinoma organoids, non-tumorous adjacent tissue-derived and healthy donor-derived intrahepatic cholangiocyte organoids was determined using the PamChip® phosphotyrosine kinase microarray platform. Kinome profiles were compared and correlated with RNA sequencing and (multi-)kinase inhibitor screening of the cholangiocarcinoma organoids. Results Kinase activity profiles of individual cholangiocarcinoma organoids are different and do not cluster together. However, growth factor signaling (EGFR, PDGFRβ) and downstream effectors (MAPK pathway) are more active in cholangiocarcinoma organoids and could provide potential druggable targets. Screening of 31 kinase inhibitors revealed several promising pan-effective inhibitors and compounds that show patient-specific efficacy. Kinase inhibitor sensitivity correlated to the activity of its target kinases for several inhibitors, signifying them as potential predictors of response. Moreover, we identified correlations between drug response and kinases not directly targeted by those drugs. Conclusions In conclusion, kinome profiling is a feasible method to identify druggable targets for cholangiocarcinoma. Future studies should confirm the potential of kinase activity profiles as biomarkers for patient stratification and precision medicine.https://doi.org/10.1186/s10020-022-00498-1CholangiocarcinomaKinome profilingDrug screening |
| spellingShingle | Ruby Lieshout Alessandra V. S. Faria Maikel P. Peppelenbosch Luc J. W. van der Laan Monique M. A. Verstegen Gwenny M. Fuhler Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification Molecular Medicine Cholangiocarcinoma Kinome profiling Drug screening |
| title | Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification |
| title_full | Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification |
| title_fullStr | Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification |
| title_full_unstemmed | Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification |
| title_short | Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification |
| title_sort | kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification |
| topic | Cholangiocarcinoma Kinome profiling Drug screening |
| url | https://doi.org/10.1186/s10020-022-00498-1 |
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