{
  "abstract": "IntroductionCastration-resistant prostate cancer (CRPC) represents a lethal stage of the disease for which docetaxel (Dtx), a microtubule-stabilizing agent, remains a standard-of-care therapy. However, the rapid emergence of docetaxel resistance severely limits its clinical benefit. Given that histone deacetylase 6 (HDAC6) is a central regulator of microtubule dynamics via α-tubulin deacetylation, we hypothesized that selective HDAC6 inhibition could re-sensitize CRPC cells to Dtx.MethodsTo elucidate mechanisms driving resistance and identify actionable vulnerabilities, we established docetaxel-resistant models in two different CRPC cell lines (DU145 and 22Rv1). We evaluated the inhibitory activity and cellular target engagement of 9b, a previously developed hydroxamic acid-based 1-benzhydryl piperazine derivative, using enzymatic assays and cellular thermal shift assays (CETSA). Functional assays and RNA sequencing were performed to investigate the effects of HDAC6 inhibition on docetaxel sensitivity and associated molecular mechanisms.ResultsEnzymatic assays demonstrated that 9b potently inhibits HDAC6 (IC50 = 0.031 μM) while exhibiting lower activity against class I HDACs, including HDAC1, HDAC3, and HDAC8. Consistently, CETSA revealed preferential target engagement of HDAC6 in the cellular environment, supporting its selective HDAC6-binding profile. Functionally, 9b significantly induced α-tubulin acetylation, enforced G2/M cell cycle arrest, and impaired CRPC cell migration. Notably, combined treatment with 9b and Dtx elicited caspase-dependent synergistic cytotoxicity, effectively reversing Dtx tolerance in resistant CRPC models. Consistent with this model, genetic ablation of HDAC6 similarly sensitized resistant cells to Dtx in colony formation assays. Mechanistically, RNA sequencing revealed that HDAC6 inhibition by 9b markedly suppressed MYC-driven transcriptional programs.DiscussionThese results implicate MYC signaling as a downstream effector of HDAC6-mediated Dtx resistance. Together, these findings demonstrate that 9b is a potent and selective HDAC6 inhibitor that enhances docetaxel response in resistant CRPC models. Furthermore, our results identify HDAC6 as a potential therapeutic vulnerability in docetaxel-resistant CRPC and provide a rationale for further evaluation of selective HDAC6 inhibition in more clinically relevant models.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "Original Research",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "Ipek Bulut"
    },
    {
      "name": "Buse Cevatemre"
    },
    {
      "name": "Busra Yildirim"
    },
    {
      "name": "Dusan Ruzic"
    },
    {
      "name": "Batuhan Mert Kalkan"
    },
    {
      "name": "Arda Isiklar"
    },
    {
      "name": "Neslihan Yuksel-Catal"
    },
    {
      "name": "Baris Sergi"
    },
    {
      "name": "Beyza Nur Celik"
    },
    {
      "name": "Deniz Yildiz"
    },
    {
      "name": "Beyza Bursali"
    },
    {
      "name": "Hamzah Syed"
    },
    {
      "name": "Katarina Nikolic"
    },
    {
      "name": "Ceyda Acilan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bzt51f56z8p8w.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1916493",
  "fulltext_url": null,
  "id": "bzt51f56z8p8w",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1916493",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "feed-journal",
      "medicine/pharmacology-toxicology"
    ]
  ],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-09",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/bzt51f56z8p8w.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:20:33Z",
      "native_id": "10.3389/fphar.2026.1916493",
      "source": "feed-frontiers",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1916493"
    },
    {
      "first_seen": "2026-11-09T12:23:31Z",
      "native_id": "10.3389/fphar.2026.1916493",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1916493/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "feed-journal:medicine/pharmacology-toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "HDAC6 inhibition reverts docetaxel resistance in castration resistant prostate cancer",
  "title_text": "HDAC6 inhibition reverts docetaxel resistance in castration resistant prostate cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T18:20:19Z",
  "url": "https://research.draconitic.com/paper/bzt51f56z8p8w",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}