RT Journal Article
SR Electronic
T1 Chemoproteomic discovery of a ritanserin-targeted kinase network mediating apoptotic cell death of lung tumor cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.113001
DO 10.1124/mol.118.113001
A1 Sean T Campbell
A1 Caroline E Franks
A1 Adam L Borne
A1 Myungsun Shin
A1 Liuzhi Zhang
A1 Ku-Lung Hsu
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/08/29/mol.118.113001.abstract
AB 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 and small cell lung cancer (NSCLC, 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 (DGKα, PI4KB) and protein signaling (FER, RAF), metabolism (EF2K, E2AK4), and DNA damage response (TLK2) to broadly kill lung tumor cell types. While ritanserin exhibits polypharmacology in NSCLC proteomes, this compound shows unexpected specificity for c-RAF in the SCLC subtype with negligible activity against other kinases mediating MAPK signaling. We show 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 provide new opportunities for repositioning ritanserin in cancer.