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Molecular basis of resistance to the microtubule-depolymerizing antitumor compound plocabulin

Areti Pantazopoulou1,2, Carlos María Galmarini3, Miguel A Peñalva4

  • 1Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain. apantazopoulou@uchicago.edu.

Scientific Reports
|June 7, 2018
PubMed

Insights

Plocabulin targets fungal beta-tubulin, but resistance can arise from mutations affecting protein synthesis and mitochondrial function. These findings suggest potential biomarkers for plocabulin drug efficacy in cancer treatment.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Pharmacology

Background:

  • Plocabulin (PM060184) is a microtubule depolymerizing agent with demonstrated antiproliferative activity in solid tumors.
  • The drug exhibits potent antifungal activity against Aspergillus nidulans, highlighting conserved cellular targets.
  • Understanding plocabulin's mechanism in fungi can provide insights into its action in human cells and potential resistance pathways.

Purpose of the Study:

  • To elucidate the molecular mechanism of action and identify resistance factors for plocabulin using the genetically tractable fungus Aspergillus nidulans.
  • To investigate the role of beta-tubulin as the primary target of plocabulin.
  • To identify novel cellular pathways and proteins involved in plocabulin sensitivity and resistance.

Main Methods:

  • Genetic analysis of plocabulin resistance in Aspergillus nidulans.
  • Construction of a plocabulin-insensitive strain by combining mutations in beta-tubulin isotypes.
  • Functional screening of resistant mutants to identify genes conferring resistance.
  • Identification of mutations in eukaryotic translation initiation factor eIF2B, TIM44, and transcription factors.

Main Results:

  • Confirmation that fungal beta-tubulin is the sole molecular target of plocabulin.
  • Identification of five plocabulin-resistant mutants lacking beta-tubulin mutations.
  • Resistance mutations were found in subunits of eIF2B (General Amino Acid Control), TIM44 (mitochondrial translocase), and binuclear zinc cluster transcription factors.
  • These proteins are involved in translation initiation, mitochondrial function, and potentially drug transport.

Conclusions:

  • Fungal beta-tubulin is the essential target of plocabulin.
  • Novel resistance mechanisms involve pathways regulating protein synthesis, mitochondrial function, and drug transport.
  • Conserved proteins identified in resistance pathways may serve as biomarkers for plocabulin efficacy in cancer therapy.

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