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Significance The spindle checkpoint is required for proper chromosome segregation. Mitotic arrest deficiency 2 (Mad2), a component of the spindle checkpoint, is overexpressed in many cancer cells. This phenotype can be used to specifically kill Mad2-overexpressing tumor cells. Because the spindle checkpoint pathway is highly conserved between yeast and humans, we performed a screen to identify mutants in which Mad2 overexpression kills yeast cells. The screen revealed that Mad2 overexpression induced lethality in 13 gene deletions. Among the human homologs of the 13 candidate genes, a gene encoding protein phosphatase 2 (PP2A) significantly inhibited the growth of Mad2-overexpressing tumor cells. These results indicate that PP2A can be a specific therapeutic target in Mad2-overexpressing tumors.

Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors