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Kiseleva AA , Korobeynikov VA , Nikonova AS , Zhang P , Makhov P , Deneka AY , Einarson MB , Serebriiskii IG , Liu H , Peterson JR , Golemis EA
Unexpected activities in regulating ciliation contribute to off-target effects of targeted drugs
Clin Cancer Res. 2019 Jul 1;25(13) :4179-4193
PMID: 30867219 PMCID: PMC6606352 URL: https://www.ncbi.nlm.nih.gov/pubmed/30867219
AbstractPURPOSE: 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 non-transformed cell populations, as extracellular ligands including Sonic Hedgehog (SHH), PDGFRa, 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 pre-clinical 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 PDGFRa. In vivo, sunitinib durably limited ciliation and cilia-related 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.
NotesKiseleva, Anna A Korobeynikov, Vladislav A ORCID: https://orcid.org/0000-0002-9127-292X Nikonova, Anna S Zhang, Peishan ORCID: https://orcid.org/0000-0002-8863-9962 Makhov, Petr Deneka, Alexander Y Einarson, Margret B Serebriiskii, Ilya G Liu, Hanqing ORCID: https://orcid.org/0000-0001-7984-6305 Peterson, Jeffrey R ORCID: https://orcid.org/0000-0002-0604-718X Golemis, Erica A ORCID: https://orcid.org/0000-0003-3618-3673 P30 CA006927/CA/NCI NIH HHS/United States R01 DK108195/DK/NIDDK NIH HHS/United States R01 GM083025/GM/NIGMS NIH HHS/United States Journal Article United States Clin Cancer Res. 2019 Jul 1;25(13):4179-4193. doi: 10.1158/1078-0432.CCR-18-3535. Epub 2019 Mar 13.