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We applied a genome\u2010wide loss\u2010of\u2010function screening approach in human haploid cells to characterize genetic vulnerabilities to classical microtubule\u2010targeting agents. Using docetaxel and vinorelbine, two well\u2010established chemotherapeutic agents, we sought to identify genetic alterations sensitizing human<jats:styled-content style=\"fixed-case\">HAP<\/jats:styled-content>1 cells to these drugs. Despite the fact that both drugs act on microtubules, a set of distinct genes were identified whose disruption affects drug sensitivity. For docetaxel, this included a number of genes with a function in mitosis, while for vinorelbine we identified inactivation of<jats:italic><jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7<\/jats:italic>,<jats:italic><jats:styled-content style=\"fixed-case\">RB<\/jats:styled-content>1<\/jats:italic>, and<jats:italic><jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>2<\/jats:italic>, three frequently mutated tumor suppressor genes, as sensitizing factors. We validated these genes using independent knockout clones and confirmed<jats:italic><jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7<\/jats:italic>as an important regulator of the mitotic spindle assembly. Upon<jats:italic><jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7<\/jats:italic>depletion, vinorelbine treatment led to decreased survival of cells due to defective mitotic progression and subsequent mitotic catastrophe. We show that haploid insertional mutagenesis screens are a useful tool to study genetic vulnerabilities to classical chemotherapeutic drugs by identifying thus far unknown sensitivity factors. These results provide a rationale for investigating patient response to vinca alkaloid\u2010based anticancer treatment in relation to the mutational status of these three tumor suppressor genes, and could in the future lead to the establishment of novel predictive biomarkers or suggest new drug combinations based on molecular mechanisms of drug sensitivity.<\/jats:p>","DOI":"10.1002\/1878-0261.12307","type":"journal-article","created":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T21:24:47Z","timestamp":1524605087000},"page":"953-971","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Haploid genetic screens identify genetic vulnerabilities to microtubule\u2010targeting agents"],"prefix":"10.1002","volume":"12","author":[{"given":"Nora M.","family":"Gerhards","sequence":"first","affiliation":[{"name":"Institute of Animal Pathology Vetsuisse Faculty University of Bern 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