Targeting Vulnerabilities in Successive Cell Cycle Stages to Induce Death of PI3K-Activated Basal-Like Breast Cancer Cells

Frequent mutation of PI3K pathway genes in human tumors has stimulated large investments in therapeutic drugs targeting this pathway but clinical successes have been rare. As a result, many cancers with high PI3K pathway activity are still treated with conventional chemotherapy. By systematically analyzing responses of basal-like breast cancer cells to PI3K pathway inhibitors, we show that one drug, Torin2, is unusually effective because it inhibits both mTOR and PI3K-like kinases (PIKKs). Experiments with Torin2 and combinations of selective kinase inhibitors demonstrate that submaximal G1/S inhibition, increased S phase replication stress, and single-stranded DNA in mitosis are all involved in cell killing. Combination therapy with inhibitors of signal transduction kinases conventionally targets simultaneously active pathways. Our studies of Torin2 show that favorable combinatorial drug effects can also result from targeting successive cell cycle vulnerabilities, eliciting a cascade of deleterious effects that culminates in mitotic errors and death.