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Dual targeting of oncogenic microtubules and mitochondria in PDAC

Michael W Spinrad1, Chun Cai1,2, Lauren C Gattie1

  • 1Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Oncoscience
|February 13, 2026
PubMed

Insights

SB-216 significantly inhibits pancreatic cancer cell growth by targeting oncogenic microtubules and mitochondrial function. This dual approach suppresses key cancer drivers, offering a novel therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options.
  • Microtubule dynamics, particularly βIII- and βIVb-tubulin overexpression, are implicated in PDAC growth and metastasis.
  • Bromodomain and Extra-Terminal domain (BET) proteins, like BRD4, regulate mitochondrial function and are potential therapeutic targets.

Purpose of the Study:

  • To investigate the efficacy of SB-216 and Veru-111 in inhibiting PDAC cell growth.
  • To determine if these compounds suppress oncogenic βIII- and βIVb-tubulin subtypes and mitochondrial function via BRD4 inhibition.
  • To explore the simultaneous targeting of microtubule dynamics and mitochondrial respiration in PDAC.

Main Methods:

  • Cell growth was assessed using the IncuCyte Live-Cell Analysis system.
  • Quantitative real-time PCR and Western blot analysis were used to evaluate mRNA and protein expression of βIII-tubulin, βIVb-tubulin, and BRD4.
  • Mitochondrial respiration was measured with a Seahorse XF-24 Flux Analyzer, and autophagy/mitophagy markers were analyzed.

Main Results:

  • SB-216 and Veru-111 significantly inhibited PDAC cell growth across multiple cell lines and doses (p < .0001).
  • Treatment led to decreased mRNA expression of TUBB3 (βIII) and TUBB4 (βIVb) and reduced BRD4 protein levels.
  • Mitochondrial respiration was impaired, and autophagy markers increased in treated PDAC cells.

Conclusions:

  • SB-216 effectively inhibits PDAC cell growth by targeting both oncogenic microtubules and mitochondrial function.
  • This novel therapeutic strategy simultaneously targets two critical hallmarks of cancer progression and lethality.
  • The findings support the development of BET inhibitors like SB-216 for pancreatic cancer treatment.
Keywords:
bromo- and extra-terminal domainmitochondriamitochondrial stressmitophagypancreatic ductal adenocarcinoma

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