Some 70% of triple negative breast cancers (TNBCs)—the deadliest subtype of breast malignancies—have alterations in PI3 kinase signaling pathway members PIK3CA, AKT1 or PTEN. Researchers led by Ludwig Harvard’s Karen Cichowski reported in an October publication in Nature that a combination of two therapeutic agents, one of which targets this pathway, could drive TNBC cells into a distinctly treatable state. They discovered that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 to drive robust tumor regression in multiple mouse models of TNBC, including those derived from patient tumors. The inhibitors exert these effects by cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state. (Basal cells help circulate milk during lactation, while luminal cells in mammary glands produce milk.) This differentiation cannot be induced by either agent alone. Once TNBCs are differentiated, the agents kill them by hijacking signals that normally drive mammary gland involution, a naturally occurring process in which milk-producing cells die after the cessation of lactation. The researchers also used machine learning to predict patient responses to this strategy, which could help set the stage for clinical trials. Karen and her colleagues note that their findings illustrate how deregulated epigenetic enzymes can protect tumor cells from oncogenic vulnerabilities and how developmental cell death pathways unique to specific tissues might be exploited for cancer therapy.
AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution
Nature, 2024 October 9