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.

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.

• Authors: Monika Caban, Bettina Koblmueller, Diana Groza, Hemma H Schueffl, Alessio Terenzi, Alexander Tolios, Thomas Mohr, Marlene Mathuber, Kushtrim Kryeziu, Carola Jaunecker, Christine Pirker, Bernhard K Keppler, Walter Berger, Christian R Kowol, Petra Heffeter
• Journal: Cancer letters (Cancer Lett) Vol. 565 Pg. 216237 (07 01 2023) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 37211067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

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

Topics

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