Unraveling systemic responses to NQO1-activated IB-DNQ and Rucaparib single and dual agent therapy in triple-negative breast cancers.
| Title: | Unraveling systemic responses to NQO1-activated IB-DNQ and Rucaparib single and dual agent therapy in triple-negative breast cancers. |
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| Authors: | Runnebohm AM; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; Wijeratne HRS; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; Peck Justice SA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; Department of Biology, Marian University, Indianapolis, IN.; Wijeratne AB; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; IU Simon Comprehensive Cancer Center, Indianapolis, IN.; Roy G; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; Smith JJ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; Singh N; Charles River Laboratories, Spencerville, OH.; Hergenrother P; Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL.; Boothman DA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; IU Simon Comprehensive Cancer Center, Indianapolis, IN.; Motea EA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; IU Simon Comprehensive Cancer Center, Indianapolis, IN.; Mosley AL; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.; IU Simon Comprehensive Cancer Center, Indianapolis, IN.; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2025 Apr 08. Date of Electronic Publication: 2025 Apr 08. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Triple negative breast cancer (TNBC) is a highly aggressive breast cancer that is unresponsive to hormonal therapies. One potential TNBC-specific therapeutic target is NQO1, as it is highly expressed in many TNBC patients and lowly expressed in non-cancer tissues. Here we use a derivative of DNQ, isobutyl-deoxynyboquinone (IB-DNQ) that is more potent and specific in killing TNBC cells than NQO1-activator β-lapachone while displaying strong NQO1-dependence. We evaluated the cellular signaling changes that occur following 4-hour treatment of TNBC cells with either single agent or combination IB-DNQ and / or PARP inhibitor (Rucaparib). Short treatments (4 hours) with IB-DNQ alone or combined with the PARP inhibitor Rucaparib revealed few changes in protein abundance but significant rapid alterations in protein phosphorylation and thermal stability, with clear synergy in the combination treatment. Key phosphorylated targets linked to RNA Polymerase II inhibition and DNA damage response were altered during our short time treatment. Thermal proteome profiling (TPP) identified novel, combination-specific changes in protein biophysical state suggesting new therapeutic vulnerabilities in TNBC cells. Our findings highlight how even brief treatments can uncover distinct biophysical protein changes via TPP, offering a resource for mechanistic studies of IB-DNQ mechanism of action and the development of NQO1-activated therapeutics for TNBC treatment. |
| Competing Interests: | Competing interests The authors declare that they have no competing interests. |
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| Grant Information: | UL1 TR002529 United States TR NCATS NIH HHS; P30 CA082709 United States CA NCI NIH HHS; R01 NS121550 United States NS NINDS NIH HHS; F30 AG079580 United States AG NIA NIH HHS; R01 CA221158 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: DNA damage; IB-DNQ; Rucaparib; Triple negative breast cancer; cell cycle; mass spectrometry; multiomics; phosphoproteomics; transcription |
| Entry Date(s): | Date Created: 20240527 Latest Revision: 20260301 |
| Update Code: | 20260301 |
| PubMed Central ID: | PMC11118307 |
| DOI: | 10.1101/2024.05.15.594427 |
| PMID: | 38798459 |
| Database: | MEDLINE |
Journal Article; Preprint