Abstract B039: KDM4B inhibition confers suseptibility to PI3K inhibitor in PTEN-deficient TNBC through overactivating UPR pathway

Abstract

Abstract Triple-negative breast cancer (TNBC) is among the most lethal cancers in females. Up to 35% of TNBC show PTEN mutation or PTEN loss (PTEN deficiency). Although PTEN deficiency leads to aberrant activation of PI3K/AKT signaling, therapeutic targeting of PI3K/AKT pathway has yielded very limited clinical benefit. The effective therapeutic targets for PTEN-deficient cancers are in urgent need of identifying common vulnerabilities of this important pathway. To identify additional chemical drugs that target PTEN-deficient TNBC, we performed a drug screening together with a series of in vitro and in vivo validation. Here, we show that PTEN deficiency confers vulnerability to inhibition of histone demethylase KDM4B, resulting from perturbation of endoplasmic reticulum (ER) homeostasis through activating eIF2α/ATF4 unfolded protein response (UPR) pathway. Mechanistically, KDM4B suppresses UPR pathway by interacting with and inhibiting eIF2α activation, and this function requires its demethylase activity but is independent of histone modification. Consistent with the sensitivity, PTEN-deficient cells and samples from PTEN-deficient patients show constitutively activation of UPR, which usually confers survival advantage but induces cell death once it is further activated and prolonged by KDM4B inhibition. More importantly, targeting KDM4B can robustly synergize with PI3K inhibitor to induce cell death in PTEN-deficient TNBC. This synergistic killing is caused by "overactivating" the UPR pathway resulting from transcriptional activation of UPR genes by ATF4 and FoxO1. Collectively, our study thus identifies a novel cytoplasmic function of KDM4B in regulating cellular stress and provides a new therapeutic approach to treat PTEN-deficient TNBC. Citation Format: Wenyu Wang, Gokce Oguz, Puay Leng Lee, Siti Maryam Yatim, Qiang Yu. KDM4B inhibition confers suseptibility to PI3K inhibitor in PTEN-deficient TNBC through overactivating UPR pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B039.