Abstract
Purpose: For many tumors, signaling exchanges between cancer cells and other cells in their microenvironment influence overall tumor signaling. Some of these exchanges depend on expression of the primary cilium on nontransformed cell populations, as extracellular ligands including Sonic Hedgehog (SHH), PDGFRα, and others function through receptors spatially localized to cilia. Cell ciliation is regulated by proteins that are themselves therapeutic targets. We investigated whether kinase inhibitors of clinical interest influence ciliation and signaling by proteins with ciliary receptors in cancer and other cilia-relevant disorders, such as polycystic kidney disease (PKD). Experimental Design: We screened a library of clinical and preclinical kinase inhibitors, identifying drugs that either prevented or induced ciliary disassembly. Specific bioactive protein targets of the drugs were identified by mRNA depletion. Mechanism of action was defined, and activity of select compounds investigated. Results: We identified multiple kinase inhibitors not previously linked to control of ciliation, including sunitinib, erlotinib, and an inhibitor of the innate immune pathway kinase, IRAK4. For all compounds, activity was mediated through regulation of Aurora-A (AURKA) activity. Drugs targeting cilia influenced proximal cellular responses to SHH and PDGFRα. In vivo, sunitinib durably limited ciliation and ciliarelated biological activities in renal cells, renal carcinoma cells. and PKD cysts. Extended analysis of IRAK4 defined a subset of innate immune signaling effectors potently affecting ciliation. Conclusions: These results suggest a paradigm by which targeted drugs may have unexpected off-target effects in heterogeneous cell populations in vivo via control of a physical platform for receipt of extracellular ligands.
Original language | English |
---|---|
Pages (from-to) | 4179-4193 |
Number of pages | 15 |
Journal | Clinical Cancer Research |
Volume | 25 |
Issue number | 13 |
DOIs | |
State | Published - 2019 |
Keywords
- Animals
- Biomarkers
- Cell Line
- Cilia/drug effects
- Disease Susceptibility
- Drug Discovery
- Erlotinib Hydrochloride/pharmacology
- Hedgehog Proteins/metabolism
- Humans
- Kidney Diseases, Cystic/etiology
- Mice
- Models, Biological
- Paracrine Communication/drug effects
- Platelet-Derived Growth Factor/metabolism
- Polycystic Kidney, Autosomal Dominant/metabolism
- Protein Kinase Inhibitors/pharmacology
- RNA, Small Interfering/genetics
- Signal Transduction/drug effects
- Small Molecule Libraries
- Sunitinib/pharmacology
Fingerprint
Dive into the research topics of 'Unexpected activities in regulating ciliation contribute to off-target effects of targeted drugs'. Together they form a unique fingerprint.Equipment
-
Biological Imaging Facility
Gligorijevic, PhD, B. (Director), Johnson, PhD, N. (Director), Efimov, PhD, A. (Manager) & Yang, PhD, Y. (Manager)
Equipment/facility: Facility
-
Cell Culture Facility
Campbell, PhD, K. S. (Director) & Kwok, PhD, T. (Manager)
Equipment/facility: Facility
-
Cell Sorting Facility
Campbell, PhD, K. S. (Director), Font-Burgada, PhD, J. (Director), MacFarlane, PhD, A. (Manager) & Oesterling, BS, J. (Manager)
Equipment/facility: Facility