KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer

Wang et al. report an unexpected role of demethylase KDM4B in regulating unfolded protein response (UPR). A stepwise hyperactivation of UPR by co-targeting the KDM4B and PI3K pathway uncovers a therapeutic vulnerability of PTEN-deficient TNBC that otherwise would be resistant to PI3K inhibition.
PTEN deficiency in breast cancer leads to resistance to PI3K–AKT inhibitor treatment despite aberrant activation of this signaling pathway. Here, we report that genetic depletion or small molecule inhibition of KDM4B histone demethylase activates the unfolded protein response (UPR) pathway and results in preferential apoptosis in PTEN-deficient triple-negative breast cancers (TNBCs). Intriguingly, this function of KDM4B on UPR requires its demethylase activity but is independent of its canonical role in histone modification, and acts through its cytoplasmic interaction with eIF2α, a crucial component of UPR signaling, resulting in reduced phosphorylation of this component. Targeting KDM4B in combination with PI3K inhibition induces further activation of UPR, leading to robust synergy in apoptosis. These findings identify KDM4B as a therapeutic vulnerability in PTEN-deficient TNBC that otherwise would be resistant to PI3K inhibition.
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