biostudies-literatureRao SLinde Family GiftJonathan M. Goldstein and Kaia Miller Goldstein Systems Pharmacology FellowshipNHLBI NIH HHSNCI NIH HHSHHS National Institutes of Health (NIH)NIGMS NIH HHS8664-8673https://www.ebi.ac.uk/biostudies/studies/S-EPMC6544847biostudies-literatureUnknown294(21)Most cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this study, we developed a non-genetic strategy for the identification of pathways that drive cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multitargeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof of coThe Journal of biological chemistryA multitargeted probe-based strategy to identify signaling vulnerabilities in cancers.PMC6544847U54-CA225088U54-HL127365P50GM107618U54 CA225088P50 GM107618U54 HL127365Rao SSorger PKGray NSHafner MSubramanian KDu GfalseA multitargeted probe-based strategy to identify signaling vulnerabilities in cancers.Most cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this study, we developed a non-genetic strategy for the identification of pathways that drive cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multitargeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof of co2019-01-01T00:00:00Z2019 May2025-04-04T19:04:31.791Z2019-07-01T13:57:27ZS-EPMC65448473085817910.1074/jbc.ra118.00680510.1074/jbc.RA118.006805