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Abstract
Ritanserin was tested in the clinic as a serotonin receptor inverse agonist but recently emerged as a novel kinase inhibitor with potential applications in cancer. Here, we discovered that ritanserin induced apoptotic cell death of non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells via a serotonin-independent mechanism. We used quantitative chemical proteomics to reveal a ritanserin-dependent kinase network that includes key mediators of lipid [diacylglycerol kinase α, phosphatidylinositol 4-kinase β] and protein [feline encephalitis virus-related kinase, rapidly accelerated fibrosarcoma (RAF)] signaling, metabolism [eukaryotic elongation factor 2 kinase, eukaryotic translation initiation factor 2-α kinase 4], and DNA damage response [tousled-like kinase 2] to broadly kill lung tumor cell types. Whereas ritanserin exhibited polypharmacology in NSCLC proteomes, this compound showed unexpected specificity for c-RAF in the SCLC subtype, with negligible activity against other kinases mediating mitogen-activated protein kinase signaling. Here we show that ritanserin blocks c-RAF but not B-RAF activation of established oncogenic signaling pathways in live cells, providing evidence in support of c-RAF as a key target mediating its anticancer activity. Given the role of c-RAF activation in RAS-mutated cancers resistant to clinical B-RAF inhibitors, our findings may have implications in overcoming resistance mechanisms associated with c-RAF biology. The unique target landscape combined with acceptable safety profiles in humans provides new opportunities for repositioning ritanserin in cancer.
Footnotes
- Received May 15, 2018.
- Accepted August 23, 2018.
↵1 S.T.C., C.E.F., and A.L.B. contributed equally to this work.
This work was supported by the University of Virginia [Startup Funds (to K.-L.H.)], the National Institutes of Health National Institute on Drug Abuse [Grants DA035864 and DA043571 (to K.-L.H.)], the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM007055 (to C.E.F.)], the National Institutes of Health National Cancer Institute [Grant T32-CA009109 (to A.L.B. and S.T.C.)], the Schiff Foundation [Brain Tumor Research Award (to K.-L.H.)], and the U.S. Department of Defense [Grant W81XWH-17-1-0487 (to K.-L.H.)].
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics