Jiahong Tan

LOXL2 reduces susceptibility to PARP inhibitors by promoting super-enhancer-regulated DNA damage repair in high-grade serous ovarian cancer

Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of homologous recombination-deficient (HRD) tumors, yet their efficacy in homologous recombination-proficient (HRP) tumors is still limited. Here, we pinpoint lysyl oxidase-like 2 (LOXL2) as a key epigenetic regulator driving PARPi resistance. Our study demonstrate that elevated LOXL2 expression correlates with poor prognosis and disease recurrence in high-grade serous ovarian cancer (HGSOC) patients. Functional studies reveal that LOXL2 depletion or pharmacological inhibition synergizes with PARPi to suppress HRP models of both ovarian and breast cancer. Mechanistically, LOXL2 directly interacts with and transcriptionally activates BRD4, a core component of the super-enhancer complex, thereby amplifying the expression of DNA damage repair (DDR) genes such as MDC1, KAT5, and USP7. Strikingly, LOXL2 inhibition induces a "BRCAness" phenotype in HRP tumors, rendering them more susceptible to PARPi by impairing DDR capacity. Combining BET inhibitors with PARPi abrogates LOXL2-mediated resistance, underscoring BRD4 dependency in this process. Our findings establish LOXL2 as a druggable epigenetic target to overcome PARPi resistance in HRP models of multiple tumor types, presenting a therapeutic strategy independent of HR status and holding significant clinical potential for expanding PARPi benefits to a broader patient population.

C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer

AbstractPARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.