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

doi:10.1186/s10020-022-00498-1

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

Mol Med. 2022 Jun 28;28(1):74. doi: 10.1186/s10020-022-00498-1.

Authors

Ruby Lieshout^#¹, Alessandra V S Faria^#^{2

3}, Maikel P Peppelenbosch², Luc J W van der Laan¹, Monique M A Verstegen^#¹, Gwenny M Fuhler^#⁴

Affiliations

¹ Erasmus MC Transplant Institute, Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
² Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
³ Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas, Brazil.
⁴ Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. g.fuhler@erasmusmc.nl.

^# Contributed equally.

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.

Keywords: Cholangiocarcinoma; Drug screening; Kinome profiling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Duct Neoplasms* / drug therapy
Bile Ducts, Intrahepatic
Cholangiocarcinoma* / drug therapy
Humans
Organoids
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use

Substances

Protein Kinase Inhibitors