Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma

JCI Insight. 2019 Oct 3;4(19):e131106. doi: 10.1172/jci.insight.131106.

Abstract

Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.

Keywords: Head and neck cancer; Metabolism; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Transport System ASC / genetics
  • Amino Acid Transport System ASC / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cetuximab / pharmacology*
  • Dichloroacetic Acid / antagonists & inhibitors
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Mice, Nude
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / drug effects
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism*
  • Signal Transduction
  • Squamous Cell Carcinoma of Head and Neck / drug therapy
  • Squamous Cell Carcinoma of Head and Neck / genetics*
  • Squamous Cell Carcinoma of Head and Neck / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Amino Acid Transport System ASC
  • Antineoplastic Agents
  • Minor Histocompatibility Antigens
  • PDK1 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • SLC1A5 protein, human
  • Dichloroacetic Acid
  • EGFR protein, human
  • ErbB Receptors
  • Cetuximab