A novel EGFR inhibitor acts as potent tool for hypoxia-activated prodrug systems and exerts strong synergistic activity with VEGFR inhibition in vitro and in vivo

Cancer Lett. 2023 Jul 1:565:216237. doi: 10.1016/j.canlet.2023.216237. Epub 2023 May 19.

Abstract

Small-molecule EGFR inhibitors have distinctly improved the overall survival especially in EGFR-mutated lung cancer. However, their use is often limited by severe adverse effects and rapid resistance development. To overcome these limitations, a hypoxia-activatable Co(III)-based prodrug (KP2334) was recently synthesized releasing the new EGFR inhibitor KP2187 in a highly tumor-specific manner only in hypoxic areas of the tumor. However, the chemical modifications in KP2187 necessary for cobalt chelation could potentially interfere with its EGFR-binding ability. Consequently, in this study, the biological activity and EGFR inhibition potential of KP2187 was compared to clinically approved EGFR inhibitors. In general, the activity as well as EGFR binding (shown in docking studies) was very similar to erlotinib and gefitinib (while other EGFR-inhibitory drugs behaved different) indicating no interference of the chelating moiety with the EGFR binding. Moreover, KP2187 significantly inhibited cancer cell proliferation as well as EGFR pathway activation in vitro and in vivo. Finally, KP2187 proved to be highly synergistic with VEGFR inhibitors such as sunitinib. This indicates that KP2187-releasing hypoxia-activated prodrug systems are promising candidates to overcome the clinically observed enhanced toxicity of EGFR-VEGFR inhibitor combination therapies.

Keywords: Cancer therapy; Cobalt; EGFR; Hypoxia; Prodrug; Tyrosine kinase inhibitor; VEGFR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / pharmacology
  • Humans
  • Hypoxia / metabolism
  • Lung Neoplasms* / metabolism
  • Prodrugs* / pharmacology
  • Prodrugs* / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use

Substances

  • Prodrugs
  • ErbB Receptors
  • Protein Kinase Inhibitors
  • Erlotinib Hydrochloride
  • Antineoplastic Agents
  • EGFR protein, human