Abstract
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.
Similar content being viewed by others
Data availability
The Cancer Genome Atlas data were accessed via cbioportal. Caris Genomics data were accessed through the Caris Precision Oncology Alliance.
Code availability
R script used in the data analysis was provided in the Supplementary Information. TCGA data analysis used the cbioportal built-in tools for group comparison. Caris data analysis used built-in tools available from the Caris CODEai portal.
References
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Drew, Y. et al. Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2. J. Natl. Cancer Inst. 103, 334–346 (2011).
McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).
Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).
Veeck, J. et al. BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors. J. Clin. Oncol. 28, e563–e564 (2010). author reply e5-6.
Hughes-Davies, L. et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115, 523–535 (2003).
Audeh, M. W. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376, 245–251 (2010).
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).
Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376, 235–244 (2010).
Ledermann, J. et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 366, 1382–1392 (2012).
Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, 852–861 (2014).
Livraghi, L. & Garber, J. E. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 13, 188 (2015).
Ramakrishnan Geethakumari, P., Schiewer, M. J., Knudsen, K. E. & Kelly, W. K. PARP inhibitors in prostate cancer. Curr. Treat. Options Oncol. 18, 37 (2017).
Bhalla, A. & Saif, M. W. PARP-inhibitors in BRCA-associated pancreatic cancer. JOP 15, 340–343 (2014).
Levra, M. G., Olaussen, K. A., Novello, S. & Soria, J. C. PARP inhibitors: an interesting pathway also for non-small cell lung cancer? Curr. Pharm. Des. 20, 3875–3882 (2014).
Plummer, R. et al. A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother. Pharm. 71, 1191–1199 (2013).
Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).
Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016).
Fojo, T. & Bates, S. Mechanisms of resistance to PARP inhibitors-three and counting. Cancer Discov. 3, 20–23 (2013).
Lord, C. J. & Ashworth, A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat. Med. 19, 1381–1388 (2013).
Benafif, S. & Hall, M. An update on PARP inhibitors for the treatment of cancer. Onco Targets Ther. 8, 519–528 (2015).
Miura, K. et al. The combination of olaparib and camptothecin for effective radiosensitization. Radiat. Oncol. 7, 62 (2012).
Al-Ejeh, F. et al. Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor. J. Nucl. Med. 54, 913–921 (2013).
Evers, B. et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res. 14, 3916–3925 (2008).
Norris, R. E., Adamson, P. C., Nguyen, V. T. & Fox, E. Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors. Pediatr. Blood Cancer 61, 145–150 (2014).
Zander, S. A. et al. Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 70, 1700–1710 (2010).
Liu, J. F. et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 15, 1207–1214 (2014).
Wang, D. et al. Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes. Gynecol. Oncol. 142, 548–556 (2016).
Wang, D. et al. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer. Oncotarget 7, 13153–13166 (2016).
Liu, L. et al. TGFbeta induces “BRCAness” and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes. Mol. Cancer Res. 12, 1597–1609 (2014).
Gadducci, A. & Guerrieri, M. E. PARP inhibitors alone and in combination with other biological agents in homologous recombination deficient epithelial ovarian cancer: from the basic research to the clinic. Crit. Rev. Oncol. Hematol. 114, 153–165 (2017).
Samol, J. et al. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Investig. New Drugs 30, 1493–1500 (2012).
Fang, P. et al. Olaparib-induced adaptive response is disrupted by FOXM1 targeting that enhances sensitivity to PARP Inhibition. Mol. Cancer Res. 16, 961–973 (2018).
Wang, M. & Gartel, A. L. Micelle-encapsulated thiostrepton as an effective nanomedicine for inhibiting tumor growth and for suppressing FOXM1 in human xenografts. Mol. Cancer Ther. 10, 2287–2297 (2011).
Buchner, M. et al. Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia. Nat. Commun. 6, 6471 (2015).
Jiang, L. et al. Targeting FoxM1 by thiostrepton inhibits growth and induces apoptosis of laryngeal squamous cell carcinoma. J. Cancer Res. Clin. Oncol. 141, 971–981 (2015).
Zhang, X. et al. Targeting of mutant p53-induced FoxM1 with thiostrepton induces cytotoxicity and enhances carboplatin sensitivity in cancer cells. Oncotarget 5, 11365–11380 (2014).
Gartel, A. L. Thiostrepton, proteasome inhibitors and FOXM1. Cell cycle 10, 4341–4342 (2011).
Aminake, M. N. et al. Thiostrepton and derivatives exhibit antimalarial and gametocytocidal activity by dually targeting parasite proteasome and apicoplast. Antimicrob. Agents Chemother. 55, 1338–1348 (2011).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).
Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).
Shi, J. & Vakoc, C. R. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell 54, 728–736 (2014).
Li, G. Q. et al. Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. Oncotarget 7, 2462–2474 (2016).
McCleland, M. L. et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J. Clin. Investig. 126, 639–652 (2016).
Shu, S. et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529, 413–417 (2016).
French, C. A. et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27, 2237–2242 (2008).
Da Costa, D. et al. BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia. Blood Cancer J. 3, e126 (2013).
Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).
Sun, L. & Gao, P. Small molecules remain on target for c-Myc. Elife 6, e22915 (2017).
Koh, C. M., Sabo, A. & Guccione, E. Targeting MYC in cancer therapy: RNA processing offers new opportunities. Bioessays 38, 266–275 (2016).
Knoechel, B. et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat. Genet. 46, 364–370 (2014).
Korkut, A. et al. Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife 4, e04640 (2015).
Zhang, Z. et al. BET bromodomain inhibition as a therapeutic strategy in ovarian cancer by downregulating FoxM1. Theranostics 6, 219–230 (2016).
Raychaudhuri, P. & Park, H. J. FoxM1: a master regulator of tumor metastasis. Cancer Res. 71, 4329–4333 (2011).
Kwok, J. M. et al. FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol. Cancer Res. 8, 24–34 (2010).
Monteiro, L. J. et al. The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment. Oncogene 32, 4634–4645 (2013).
Itzen, F., Greifenberg, A. K., Bosken, C. A. & Geyer, M. Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic Acids Res. 42, 7577–7590 (2014).
Kumar, S. et al. Coiled-coil and C2 domain-containing protein 1A (CC2D1A) promotes chemotherapy resistance in ovarian cancer. Front. Oncol. 9, 986 (2019).
Hu, W. et al. Notch3 pathway alterations in ovarian cancer. Cancer Res. 74, 3282–3293 (2014).
Garnier, J. M., Sharp, P. P. & Burns, C. J. BET bromodomain inhibitors: a patent review. Expert Opin. Ther. Pat. 24, 185–199 (2014).
Mio, C. et al. BET proteins regulate homologous recombination-mediated DNA repair: BRCAness and implications for cancer therapy. Int. J. Cancer 144, 755–766 (2019).
Zhang, N. et al. FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin. Cancer Res.18, 5961–5971 (2012).
Tan, Y., Raychaudhuri, P. & Costa, R. H. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol. Cell. Biol. 27, 1007–1016 (2007).
Ihnen, M. et al. Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer. Mol. Cancer Ther. 12, 1002–1015 (2013).
Johnson, N. et al. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. Proc. Natl. Acad. Sci. USA 110, 17041–17046 (2013).
Zhou, B. et al. Discovery of a small-molecule degrader of bromodomain and extra-terminal (BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J. Med. Chem. 61, 462–481 (2018).
Michelena, J. et al. Analysis of PARP inhibitor toxicity by multidimensional fluorescence microscopy reveals mechanisms of sensitivity and resistance. Nat. Commun. 9, 2678 (2018).
Karakashev, S. et al. BET bromodomain inhibition synergizes with PARP inhibitor in epithelial ovarian cancer. Cell Rep. 21, 3398–3405 (2017).
Sun, C. et al. BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency. Cancer Cell 33, 401–16.e8 (2018).
Yang, L. et al. Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci. Transl. Med. 9, eaal1645 (2017).
Xu, W. et al. NFATC1 promotes cell growth and tumorigenesis in ovarian cancer up-regulating c-Myc through ERK1/2/p38 MAPK signal pathway. Tumour Biol. 37, 4493–4500 (2016).
Domcke, S., Sinha, R., Levine, D. A., Sander, C. & Schultz, N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat. Commun. 4, 2126 (2013).
Garcia, P. L. et al. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene 35, 833–845 (2016).
Stordal, B. et al. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation. Mol. Oncol. 7, 567–579 (2013).
Elstrodt, F. et al. BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. Cancer Res. 66, 41–45 (2006).
Johnson, D. S., Mortazavi, A., Myers, R. M. & Wold, B. Genome-wide mapping of in vivo protein-DNA interactions. Science 316, 1497–1502 (2007).
Vichai, V. & Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc. 1, 1112–1116 (2006).
Bastola, P., Neums, L., Schoenen, F. J. & Chien, J. VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal. Mol. Oncol. 10, 1559–1574 (2016).
Bastola, P., Neums, L., Schoenen, F.J., Chien, J. VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal. Mol. Oncol. 10, 1559–1574 (2016).
Di Veroli, G. Y. et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics 32, 2866–2868 (2016).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
Andrews, G. et al. Mammalian evolution of human cis-regulatory elements and transcription factor binding sites. Science 380, eabn7930 (2023).
Acknowledgements
This work is partially funded by the University of California Davis Comprehensive Cancer Center Support Grant (JC) and T32 Training Grant, T32GM144303 (AS).
Author information
Authors and Affiliations
Contributions
P.F. and J.C. wrote the initial draft. P.F., J.C., A.S., K.M., K.J.C., and D.B. performed experimental studies and data analyses. N.J., S.W., R.A.B., and G.S.L. contributed to critical reagents and resources, reviewed the final draft, and provided their expertise in DNA repair, BRD4 targeting, and oncology.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Fang, P., Saunders, A., Minn, K. et al. BET inhibition disrupts the FOXM1-MYC axis to induce BRCAness and enhance PARP inhibitor response. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01360-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41698-026-01360-x
