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<p>Pancreatic ductal adenocarcinoma (PDAC) is an exceedingly lethal cancer that lacks actionable molecular drivers. We previously identified the transcription factor, HNF1A, as a novel driver of tumorigenesis, stemness, and metastasis in PDAC; however, HNF1A-targeting modalities do not currently exist. Here we show that HNF1A is a direct target of BRD4, with HNF1A’s expression, PDAC cell proliferation, and stemness exquisitely sensitive to BET-inhibitors (BETi), all of which can be overcome by HNF1A re-expression in a panel of PDAC cell models. RNA-sequencing analyses revealed that a subset of BETi-responsive transcripts is dependent on HNF1A expression, including multiple components of EGFR/ERBB3-signaling, with EGFR-inhibitors able to overcome HNF1A’s protective effects. We found that expressions of HNF1A, BRD4, and ERBB3 were strongly correlated across PDAC patient samples, further supporting the relevancy of this regulatory axis to the disease. These findings establish HNF1A as a novel, critical target and determinant of BETi in PDAC.</p>

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HNF1A is a novel BRD4 target and critical for BET-inhibitor response in pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Kennedy S. Humphrey,
  • Katherine J. Crawford,
  • Bharani Muppavarapu,
  • Melanie M. Mayberry,
  • William Morris,
  • Evan Torres,
  • Mark D. Long,
  • Jianxin Wang,
  • Erik S. Knudsen,
  • Agnieszka K. Witkiewicz,
  • Ethan V. Abel

摘要

Pancreatic ductal adenocarcinoma (PDAC) is an exceedingly lethal cancer that lacks actionable molecular drivers. We previously identified the transcription factor, HNF1A, as a novel driver of tumorigenesis, stemness, and metastasis in PDAC; however, HNF1A-targeting modalities do not currently exist. Here we show that HNF1A is a direct target of BRD4, with HNF1A’s expression, PDAC cell proliferation, and stemness exquisitely sensitive to BET-inhibitors (BETi), all of which can be overcome by HNF1A re-expression in a panel of PDAC cell models. RNA-sequencing analyses revealed that a subset of BETi-responsive transcripts is dependent on HNF1A expression, including multiple components of EGFR/ERBB3-signaling, with EGFR-inhibitors able to overcome HNF1A’s protective effects. We found that expressions of HNF1A, BRD4, and ERBB3 were strongly correlated across PDAC patient samples, further supporting the relevancy of this regulatory axis to the disease. These findings establish HNF1A as a novel, critical target and determinant of BETi in PDAC.