Molecular Targeting of Growth Factor Receptor Signaling in Radiation Oncology.
Ionizing radiation has been shown to activate and interact with multiple growth factor receptor pathways that can influence tumor response to therapy. Among these receptor interactions, the epidermal growth factor receptor (EGFR) has been the most extensively studied with mature clinical applications during the last decade. The combination of radiation and EGFR-targeting agents using either monoclonal antibody (mAb) or small-molecule tyrosine kinase inhibitor (TKI) offers a promising approach to improve tumor control compared to radiation alone. Several underlying mechanisms have been identified that contribute to improved anti-tumor capacity after combined treatment. These include effects on cell cycle distribution, apoptosis, tumor cell repopulation, DNA damage/repair, and impact on tumor vasculature. However, as with virtually all cancer drugs, patients who initially respond to EGFR-targeted agents may eventually develop resistance and manifest cancer progression. Several potential mechanisms of resistance have been identified including mutations in EGFR and downstream signaling molecules, and activation of alternative member-bound tyrosine kinase receptors that bypass the inhibition of EGFR signaling. Several strategies to overcome the resistance are currently being explored in preclinical and clinical models, including agents that target the EGFR T790 M resistance mutation or target multiple EGFR family members, as well as agents that target other receptor tyrosine kinase and downstream signaling sites. In this chapter, we focus primarily on the interaction of radiation with anti-EGFR therapies to summarize this promising approach and highlight newly developing opportunities.
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA.|Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, WIMR 3136, 1111 Highland Ave Madison, Madison, WI, 53705, USA.
Shyhmin
S
Huang
Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, Röntgenweg, 72076, Tübingen, Germany.
H
H
Peter Rodemann
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA. harari@humonc.wisc.edu.
Paul M
PM
Harari
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use; D059248:Chemoradiotherapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D018787:Radiation Oncology / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D000068818:Cetuximab
Growth factor receptors; Molecular targeting; Radiation