Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status [RNA-seq]

PARP inhibition has been approved as a compelling strategy for treating multiple human cancers bearing homologous recombination defects (HRD). However, due to the lack of functional biomarkers of PARPi response beyond known genetic mutations in HRD genes, expanding the potential benefit of PARP inhibitors, as well as the identification of effective therapeutic strategies for treating PARPi-resistant cancers remain urgent unmet needs. Here, we report high levels of FoxO1, either at basal expression or upon induction by PARPi, render both BRCA-proficient (BP) and BRCA-deficient (BD) human cancers resistant to PAPRi via modulating transcriptomic signature regulating DNA damage response (DDR). We further elucidated that PARPi-induced STAT3 activation, which occurred through its attenuated dephosphorylation at Y705, resulted in enhanced FoxO1 transcription via recruiting TOP2A, a downstream target of FoxO1. TOP2A orchestrated STAT3-dependent transcriptional program via facilitating RNA Pol II recruitment to gene promoters, as well as promoter-proximal pausing and pause release. Intriguingly, STAT3 inhibitor exhibits a potent synergistic effect with PARPi in treating BP or BD PAPRi-resistant PDX models across cancer types. Our data highlight a potential role of FoxO1 serving as both predictive and prognostic marker for PARPi treatment, and reveal the potency of combination treatment strategy using STAT3 inhibitor with PARPi in sensitizing PARPi-resistant cancers, regardless of BRCA status.