BET inhibition disrupts the FOXM1-MYC axis to induce BRCAness and enhance PARP inhibitor response

npj Precision Oncology · 2026-03-12

Homologous recombination (HR) proficiency underlies intrinsic and acquired resistance to PARP inhibitors (PARPi). We identify a BRD4-dependent FOXM1-MYC transcriptional axis that sustains HR gene expression and limits PARPi response. ENCODE analyses revealed extensive co-occupancy of FOXM1 and MYC at regulatory regions of DNA repair genes, including BRCA1/2 and RAD51 paralogs, suggesting a shared HR program. Functionally, transient knockdown of FOXM1 or MYC reduced BRCA1/RAD51 transcripts, whereas sustained FOXM1 silencing triggered adaptive MYC upregulation that preserved HR output, indicating compensatory control. BET inhibition with (+)-JQ1 diminished FOXM1/MYC promoter occupancy at BRCA1 and RAD51, downregulated HR genes, and synergized with PARPi in viability and clonogenic assays. A BRD4 degrader (ZBC260) achieved potent BRD4 depletion at low nanomolar doses, suppressed FOXM1/MYC and HR gene expression, enhanced PARP1 trapping, and produced strong synergy with olaparib, including in patient-derived cancer cells. Clinically, BRD4 is highly expressed in ovarian cancer and independently predicts poor survival, outperforming FOXM1 and MYC. These data establish BRD4-directed disruption of the FOXM1-MYC axis as a strategy to induce "BRCAness" and broaden PARPi efficacy.

Differential effects of GPX4 inhibitor on drug-tolerant persister ovarian cancer cells

Gynecologic Oncology · 2026-04-23

Fusobacterium nucleatum and Its Impact on Colorectal Cancer Chemoresistance: A Meta-Analysis of In Vitro Co-Culture Infections

Cancers · 2025-10-07 · 3 citations

Introduction: Fusobacterium nucleatum, a common oral microbe associated with periodontal disease, has emerged as a significant prognostic indicator in colorectal cancer (CRC). This organism is notably enriched in CRC tissues and is associated with reduced survival times and relapse. Fusobacterium is implicated in encouraging the development of chemoresistance through diverse tumor-promoting pathways that are increasingly being elucidated across molecular domains. Methods: This work uses a combined analysis of public data examining the role of F. nucleatum in CRC by investigating multiple transcriptomic datasets derived from co-culture infections in vitro. Results: In tandem with previously identified mechanisms known to be influenced by F. nucleatum, this analysis revealed that the bacterium activates multiple chemoresistance-associated pathways, including those driving inflammation, immune evasion, DNA damage, and metastasis. Notably, this study uncovered a novel induction of type I and type II interferon signaling, suggesting activation of a pseudo-antiviral state. Furthermore, pathway analysis (IPA) predicted altered regulation of several therapeutic agents, suggesting that F. nucleatum may compromise drug efficacy through transcriptional reprogramming. Conclusions: These findings reinforce the role of F. nucleatum in modulating host cellular pathways and support the hypothesis that bacterial association potentiates chemoresistance.

Abstract A046: Functional genetic screen of TP53 mutants reveals APR-246 sensitivity is mediated by p53 independent effects

Cancer Research · 2025-09-19

Abstract TP53, often referred to as the guardian of the genome, is one of the most frequently mutated genes in human cancers. High grade serous ovarian cancer (HGSOC) has a TP53 mutation rate of up to 96%. Given its multi-faceted role in human cancers, there have been many efforts to therapeutically target mutant p53. APR-246 is a small molecule drug that is proposed to bind mutant p53 and promote its thermodynamic stabilization, allowing the tumor suppressor to regain wild-type-like conformation and functionality. However, the mechanism of this drug has remained a contentious topic, as it has been shown to act via various p53-independent mechanisms, including modulation of the redox system. To address this, we have performed a systematic functional genetic screening for the identification of APR-246 rescuable p53 mutants. Our approach leverages a pooled TP53 mutagenesis library containing ∼8,000 amino acid variants, spanning the entirety of the TP53 coding sequence. Cell based screenings against sub-lethal doses of APR-246 in two ovarian cancer cell lines, SKOV3 and OVCAR5, has revealed that sensitivity to this drug is cell-line dependent rather than mutant p53-dependent. Our results suggest that p53-independent factors such as intrinsic resistance to ferroptosis may play a more significant role in response to APR-246. We propose that resistance to ferroptosis provides cellular conditions which enable identification of p53 mutants that are sensitive to APR-246. This is evidenced by our results which show that genetic screen in OVCAR5, which is more intrinsically resistant to ferroptosis, uncovers a greater number of potentially sensitive mutants, including R175H, a mutant largely recognized as rescuable by APR-246. Further, we have identified GPX4, an anti-ferroptosis gene, as a key determinant of APR-246 sensitivity. Indeed, we demonstrate synergy between APR-246 and GPX4 inhibitor, ML-210. These studies support the hypothesis that APR-246 efficacy is largely attributable to p53-independent mechanisms and that attenuation of these off-target effect may reveal potentially sensitive p53 mutants. Citation Format: Anais Saunders, Caili Tong, Anthony N. Karnezis, Gary S. Leiserowitz, Jeremy R. Chien. Functional genetic screen of TP53 mutants reveals APR-246 sensitivity is mediated by p53 independent effects [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A046.

Abstract A050: Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications

Cancer Research · 2025-09-19

Abstract Introduction: Despite treatment advances, ovarian cancer (OC) remains the deadliest gynecological cancer, with a ∼70% mortality rate. OCs initially respond to platinum chemotherapy but often develop resistance. While PARP inhibitors improve relapse-free survival in responsive cases, they do not extend overall survival. This underscores the need for effective combination therapies beyond BRCA status. The lysosomal protein cathepsin L (CTSL) can traffic to the nucleus, where it can regulate DNA repair and serve as a chromatin modifier. We found that nucleoside analog clofarabine (CLF) induces CTSL nuclear trafficking in OC cells. Here we tested the hypothesis that accumulation nuclear CTSL (nCTSL) is a biomarker of sensitivity to DNA damaging therapy in OCs for improved therapeutic options. Methods: To determine the role of CLF induced nuclear CTSL in DNA damage and its synergy with PARP and CRM1 inhibitors in PARP inhibitor–sensitive and –resistant ovarian cancer (OC) cell lines, ex vivo cultures of ascites-derived patient OC cells (OVA-3D spheroids), primary ovarian tumors, and patient-derived xenograft (PDX) models and validated by colony formation assays. Nuclear CTSL localization was determined in subcellular fractionated lysates by western blots and immunofluorescence cytometry (IFC). Tumor regression was determined in vivo using ex vivo cultures of PDX derived cells. Results: In ovarian cancer (OC) cell lines, CLF monotherapy induced nuclear CTSL (nCTSL) in a subset of models classified as CLF-responsive (CLF-r), sensitizing them to the PARP inhibitors olaparib and rucaparib. In CLF-non-responsive (CLF-nr) models, nCTSL induction and therapeutic synergy were observed only with the CLF+olaparib combination. Synergy was detected in 47% of CLF-r and 24% of CLF-nr patient-derived ascites samples (OVA). Mechanistically, CLF induced nuclear import of CTSL via KPNB1 in CLF-r cells, while this import was triggered by the CLF+olaparib combination in CLF-nr cells. CLF also downregulated the nuclear export protein CRM1 (XPO1) in both groups. Knockdown of CTSL in either CLF-r or CLF-nr cells abrogated sensitivity to the combination. Notably, in 29% of OVA samples classified as CLF-resistant (CLF-Res), CLF failed to suppress CRM1 expression. In these cases, CRM1 inhibition with KPT8602 restored CLF+PARP inhibitor synergy. In vivo, CLF-r and CLF-nr PDX models treated with the combination exhibited increased DNA damage, reduced tumor burden, and extended survival. Conclusion: These findings identify nuclear CTSL (nCTSL) induction as a potential biomarker of response to DNA-damaging therapies. The combination of CLF and olaparib represents a promising strategy to overcome drug resistance in ovarian cancer by promoting CTSL nuclear localization and enhancing DNA damage. Citation Format: Prabhu Thirusangu, Ling Jin, Upasana Ray, Anya Zhao, Julie Staub, Xinyan Wu, Xiaonan Hou, Jamison L. VanBlaricom, Syed Mohamed Musheer Aalam, Sun-Hee Lee, Ann Oberg, Nagarajan Kannan, John Weroha, Jeremy Chien, Scott H. Kaufmann, Jamie N. Bakkum-Gamez, Viji Shridhar. Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A050.

Case Report: ESR1::CITED2 Fusion in a Malignant Uterine Tumor Resembling Ovarian Sex Cord Tumor

International Journal of Gynecological Pathology · 2025-01-09 · 2 citations

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare, typically benign uterine tumor occurring over a wide age range (mean 52.4 yr). UTROSCTs often harbor translocations between ESR1 and nuclear receptor coactivators NCOA1-NCOA3 . Here, we present a 21-yr-old woman with a 16 cm complex uterine mass on CT. Grossly, the tumor had an infiltrative appearance. Histologically, it consisted of mild to moderately atypical, spindled cells with ovoid nuclei, growing in fascicles and cords within fibrous to myxohyaline stroma, with tongue-like infiltration of the myometrium. Immunohistochemically, tumor cells were positive for AE1/AE3, ER, PR, vimentin, WT-1, and CD56, and negative for inhibin, calretinin, SMA, desmin, and CD10. Whole exome and whole transcriptome sequencing identified a pathogenic ESR1::CITED2 fusion. The tumor recurred twice (15 and 21 mo after initial surgery) in the abdomen and pelvis. Taken together, the findings suggest this tumor may represent a malignant UTROSCT variant with a novel translocation.

The Role of TP53 Mutations in the Malignant Progression of Mucinous Borderline Ovarian Tumors: A Case Report and Literature Review

International Journal of Women s Health · 2025-09-01

Background: Mucinous ovarian carcinoma (MOC) is characterized by aggressive behavior and limited responsiveness to standard chemotherapeutic regimens. The infrequent occurrence of MOC arising from mucinous borderline ovarian tumors (MBOTs) and the lack of readily identifiable diagnostic markers pose significant challenges to the development of effective treatment strategies. This report presents a case of a 26-year-old woman with MBOT progression to metastatic MOC despite aggressive surgical intervention and adjuvant chemotherapy, aiming to identify potential diagnostic and therapeutic improvements. Results: A review of the literature revealed fewer than 30 comparable cases, underscoring the absence of established guidelines for diagnosing and treating the progression of MBOT to invasive MOC, particularly with respect to the role of TP53 mutations. In our patient’s case, we observed some changes in immunohistochemical marker expression between the MBOT and the subsequent invasive MOC, including altered p53 expression. Although these changes, considered in the context of existing literature, hint at a complex transformation process potentially involving genetic and epigenetic alterations, including TP53 mutations, further detailed genomic or transcriptomic analyses would be required to confirm this in our specific case. The diagnostic process was further complicated by clinical and pathological similarities with gastrointestinal malignancies. Ultimately, disease progression necessitated adjustments to the treatment plan, despite the use of a multi-agent chemotherapy regimen consisting of paclitaxel, carboplatin, and bevacizumab. Conclusion: The transition from MBOT to MOC is characterized by intricate genetic and epigenetic alterations, especially involving TP53 mutations. This progression presents considerable diagnostic challenges due to similarities with gastrointestinal cancers. Therefore, given the strong correlation between TP53 mutations and chemoresistance, there is a pressing need to develop targeted therapies and enhance diagnostic strategies. Keywords: mucinous borderline ovarian tumors, mucinous ovarian carcinoma, TP53 mutations, chemotherapy, targeted therapy

Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications

bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-14 · 1 citations

In our efforts to enhance sensitivity to PARP inhibitors, we identified clofarabine (CLF) as a potential therapy for drug-resistant ovarian cancer and nuclear trafficking of Cathepsin L (CTSL) as a treatment- responsive biomarker. Using PARP inhibitor-sensitive and -resistant OC cell lines, ex vivo cultures of patient-derived ovarian ascites (OVA), primary ovarian tumors, and xenografts (PDX), we found that CLF monotherapy induces nuclear CTSL (nCTSL) in CLF-responsive cells (CLF-r) and sensitizes them to PARP inhibitors olaparib and rucaparib. In CLF non-responsive cells (CLF-nr), a combination of CLF with olaparib is necessary for nCTSL trafficking and synergy. CLF+olaparib synergy was observed in 47% of CLF-r and 24% of CLF-nr OVA samples. Drug-induced nCTSL is crucial for DNA damage response, including cell cycle arrest and apoptosis. Knockdown of CTSL in both CLF-r and CLF-nr cells conferred resistance to the CLF+olaparib combination, emphasizing nCTSL's role in the DNA damage response pathway (DDR). Mechanistically, CLF facilitates CTSL nuclear import via KPNB1 in CLF-r cells. In CLF-nr cells, both olaparib and CLF are needed to facilitate CTSL nuclear import. Additionally, CLF downregulates the nuclear export protein CRM1 (XPO1) in both cohorts. Interestingly, CLF does not downregulate CRM1 in a subset of OVAs (29%), and they were classified as CLF-resistant (CLF- Res). In these samples, inhibiting CRM1 with KPT8602 restored synergy between CLF and PARP inhibitors. In vivo, CLF-r and CLF-nr PDX models exhibited enhanced DDR, reduced tumor burden, and prolonged survival with the CLF+olaparib combination. These findings suggest the CLF+olaparib combination is a promising therapeutic strategy for drug-resistant OC by inducing DDR through CTSL nuclear localization.

381P Treatment rechallenge after grade 1 trastuzumab-deruxtecan related interstitial lung disease: A real-world experience

Annals of Oncology · 2024-09-01 · 4 citations

Therapeutic efficacy of RAS inhibitor trametinib using a juvenile myelomonocytic leukemia patient-derived xenograft model

Pediatric Hematology and Oncology · 2024-04-22 · 2 citations

= 0.02). Trametinib's target as a RAS pathway inhibitor was verified by showing inhibition of ERK phosphorylation using immunoblot assays. In conclusion, trametinib monotherapy significantly prolongs survival in our JMML PDX model by inhibiting the RAS pathway. Our model can be effectively used for assessment of novel targeted treatments, including potential combination therapies, to improve JMML outcomes.