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Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status. [Whole-exome seq2]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213854 | GEO | 2025/08/31

REPOSITORIES: GEO

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

Project description: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.

2025-08-31 | GSE212431 | GEO

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

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

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

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The N6-methylation of adenosine (m6A) in FZD10 mRNA contributes to PARP inhibitor resistance

Project description:Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA (mRNA). The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers (EOC), PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/-catenin sensitizes the resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlates with an increase in homologous recombination activity. Moreover, PAPRi and Wnt/-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cells both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/-catenin pathway represents a potential strategy to overcome PARPi resistance.

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A site-specific analysis of the ADP-Ribosylome unveils Homogeneous Serine ADP-Ribosylation across wild-type and BRCA-mutant Breast Cancer cell lines

Project description:ADP-ribosylation (ADPr) signaling plays a crucial role in the DNA damage response. Inhibitors against the main enzyme catalyzing ADPr after DNA damage – PARP1 – are used as targeted therapies against breast cancers with BRCA1/2 mutations. However, development of resistance to PARP inhibitors (PARPi) is a major obstacle in treating patients. To better understand the role of ADPr in PARPi sensitivity, we used Liquid Chromatography-Mass Spectrometry (LC-MS) for systems level analysis of the ADP-ribosylome in six breast cancer cell lines with different PARPi sensitivities. We identified 1632 sites on 777 proteins, primarily on serine residues, with a high site overlap of DNA damage-related proteins across all cell lines, demonstrating high conservation in ADPr signaling after DNA damage. We furthermore observed site-specific differences in ADPr intensities in PARPi-sensitive BRCA mutants, and unique ADPr sites in PARPi-resistant BRCA mutant cells, which we notably show to have low PARG levels and longer PARP1 ADPr chains.

2024-08-02 | PXD047613 | Pride

Characterization of TNG348: a selective, allosteric USP1 inhibitor that synergizes with PARP inhibitors in tumors with DNA damage repair alterations

Project description:Inhibition of the deubiquitinating enzyme USP1 can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD) and represents a novel therapeutic strategy for the treatment of BRCA1/2 mutant cancers, potentially including patients whose tumors have primary or acquired resistance to PARP inhibitors (PARPi). Here, we present a comprehensive characterization of TNG348, an allosteric, selective, and reversible inhibitor of USP1 (USP1i). TNG348 induces dose-dependent accumulation of ubiquitinated protein substrates both in vitro and in vivo. CRISPR screens show that TNG348 exerts its anti-tumor effect by disrupting the translesion synthesis pathway of DNA damage tolerance through RAD18-dependent ub-PCNA induction. Though TNG348 and PARPi share the ability to selectively kill HRD tumor cells, CRISPR screens reveal that TNG348 and PARPi do so through discrete mechanisms. Particularly, knocking out PARP1 causes resistance to PARPi but sensitizes cells to TNG348 treatment. Consistent with these findings, combination of TNG348 with PARPi leads to synergistic anti-tumor effects in HRD tumors, resulting in tumor growth inhibition and regression in multiple mouse xenograft tumor models. Importantly, our data in human cancer models further show that the addition of TNG348 to PARPi treatment can overcome acquired PARPi resistance in vivo. While the clinical development of TNG348 has been discontinued due to unexpected liver toxicity in patients (NCT06065059), the present data provides preclinical and mechanistic support for the continued exploration of USP1 as a drug target for the treatment of patients with BRCA1/2 mutant or HRD cancers.

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Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibitor in breast cancer

Project description:The targeting of cancer stem cells (CSCs) has proven to be an effective approach for limiting tumor progression, thus necessitating the identification of new drugs with anti-CSC activity. Through a high-throughput drug repositioning screen, we identified the antibiotic Nifuroxazide (NIF) as a potent anti-CSC compound. Utilizing a click chemistry strategy, we demonstrated that NIF is a prodrug that is specifically bioactivated in breast CSCs. Mechanistically, NIF-induced CSC death is a result of a synergistic action that combines the generation of DNA interstrand crosslinks with the inhibition of the Fanconi anemia (FA) pathway activity. NIF treatment mimics FA-deficiency through the inhibition of STAT3, which we identified as a non-canonical transcription factor of FA-related genes. NIF induces a chemical HRDness in CSCs that (re)sensitizes breast cancers with innate or acquired resistance to PARP inhibitor (PARPi) in PDX models. Our results suggest that NIF may be useful in combination with PARPi for the treatment of breast tumors, regardless of their HRD status

2025-01-29 | GSE288275 | GEO

Clinical relevance of BRCA1 promoter methylation testing in ovarian cancer patients.

Project description:Homologous-recombination deficiency (HRD) is closely related to PARPi benefit in ovarian cancer (OC). The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade OC to HRD status and clinical behavior to assess its clinical relevance.

2023-04-10 | GSE229315 | GEO

Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [exome-Seq]

Project description:Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). HRD also activates the cyclic GMP–AMP synthase (cGAS)-STimulator of INterferon Genes (STING)-Interferon (IFN) pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of thirty-five breast cancer (BC) patient-derived xenografts (PDX) and mouse-derived allografts (MDA). PARPi sensitivity correlated with HRD, increased genomic instability, and activation of the cGAS-STING-IFN signaling pathway. Single-cell analyses showed that IFN signaling and IFN-based immune interactions were suppressed in preclinical models with acquired resistance to PARPi, lacking concomitant clonal expansion of functional CD8+ T cells. However, the combination of PARPi and a novel STING agonist (STINGa) increased immune infiltration and resulted in superior antitumor activity in these tumors. Notably, the efficacy of PARPi monotherapy and the combination treatment with a STINGa was dependent on Natural Killer (NK) cells. In agreement, BC patients with BRCA1/BRCA2 mutations and good responses to PARPi showed higher abundancy of CD56+ NK cells in the tumor microenvironment and treatment-engaged CD56bright NK cells in the peripheral immune compartment, compared to those with poor responses. Therefore, these findings propose the combination of PARPi and STINGa as a potential novel strategy to enhance the therapeutic response in patients with acquired PARPi resistance and highlight a pivotal role of NK cells in the PARPi antitumor activity.

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