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Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs
Anna A Kiseleva1,2, Vladislav A Korobeynikov1,3, Anna S Nikonova1
1Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Summary
Kinase inhibitors like sunitinib can unexpectedly alter cell communication by affecting primary cilia, which are crucial for signaling in cancer and polycystic kidney disease (PKD). This highlights potential off-target effects of cancer drugs.
Area of Science:
- Cell Biology
- Molecular Oncology
- Pharmacology
Background:
- Tumor microenvironment signaling is influenced by cell-cell communication.
- Primary cilia on non-cancerous cells mediate crucial signaling pathways, including Sonic Hedgehog (SHH) and PDGFRα.
- Ciliation is regulated by proteins that are potential therapeutic targets.
Purpose of the Study:
- To investigate the impact of clinically relevant kinase inhibitors on primary cilia formation and function.
- To explore off-target effects of these inhibitors in cancer and cilia-related disorders like polycystic kidney disease (PKD).
Main Methods:
- Screening of kinase inhibitors for effects on ciliation.
- Identification of drug targets using mRNA depletion.
- In vitro and in vivo assessment of drug activity on ciliation and signaling.
Main Results:
- Sunitinib, erlotinib, and an IRAK4 inhibitor were found to modulate ciliation.
- Drug activity was linked to Aurora-A (AURKA) kinase regulation.
- In vivo, sunitinib reduced ciliation in renal cells, cancer cells, and PKD cysts, impacting SHH and PDGFRα signaling.
Conclusions:
- Kinase inhibitors can unexpectedly control ciliation, a platform for extracellular ligand reception.
- This suggests a paradigm for off-target drug effects in complex biological systems.
- Targeted therapies may influence tumor microenvironment signaling through modulation of primary cilia.
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