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Al B. Benson III, MD, FACP, FASCO

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Can Kinome Profiling Influence Treatment Decisions for Patients With Cholangiocarcinoma?

By: Vanessa A. Carter, BS
Posted: Friday, September 30, 2022

The current treatment of the aggressive biliary tract cancer cholangiocarcinoma has been restricted to chemotherapy, although it offers limited clinical benefit. Consequently, Gwenny M. Fuhler, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues aimed to determine whether a commercial kinome profiling platform has the potential to predict specific targets in this disease. These data, which identified EGFR, PDGFRβ, and MAPK as possible druggable targets, were published in Molecular Medicine.

“Kinome profiling demonstrated individual kinase activity patterns for each organoid culture, confirming cholangiocarcinoma heterogeneity on a kinase activity level,” stated the investigators. “Explorative correlation analysis between these compounds and kinase activity identified correlations to expected and unexpected kinase targets, which could be further investigated as potential stratification biomarkers for kinase inhibitor sensitivity.”

Via the PamChip phosphotyrosine kinase microarray platform, kinase activity was measured in healthy donor-derived intrahepatic cholangiocyte organoids, patient-derived cholangiocarcinoma organoids, and nontumorous adjacent tissue. Multikinase inhibitor screening and RNA sequencing were compared with kinome profiles of the cholangiocarcinoma organoids.

Drug screening appeared to be useful in identifying multiple active pan-effective drugs and inhibitors that may elicit a more “selective” effect among these cholangiocarcinoma organoids. Although the kinase activity profiles of separate cholangiocarcinoma organoids did not cluster together or correlate, downstream effectors and growth factor signaling seem to be more active and may represent targets for therapy.

Specifically, of 31 screened kinase inhibitors, 8 were observed to be active pan-effective compounds and inhibitors that demonstrated patient-specific efficacy. Furthermore, the sensitivity of these kinase inhibitors seemed to correspond with the activity of its target kinases, effectively identifying them as response predictors. Of note, these investigators identified multiple correlations between kinases and drug responses that were not directly targeted by those drugs.

Disclosure: The study authors reported no conflict of interest.


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