Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification

Ruby Lieshout, Alessandra V.S. Faria, Maikel P. Peppelenbosch, Luc J.W. van der Laan, Monique M.A. Verstegen, Gwenny M. Fuhler*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number74
JournalMolecular Medicine
Volume28
Issue number1
DOIs
Publication statusPublished - 28 Jun 2022

Bibliographical note

Funding
This work was supported by grants from the São Paulo Research Foundation to AVSF (2017/08119-8 and 2018/00736-0). Furthermore, supported by the TKI-LSH (Topconsortium Kennis en Innovatie-Life Sciences & Health) grant (TIL, EMC-LSHM17064), the Netherlands Organization for Health Research and Development InnoSysTox grant (ZonMw project 114027003), and the Dutch Digestive Foundation (MLDS-Diagnostics grant D16-26).

Publisher Copyright: © 2022, The Author(s).

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