Epidermal growth factor family receptors and inhibitors: Radiation response modulators

Mechanisms of EGF family receptor dysregulation and modulation by inhibitors. (A) Autocrine/paracrine stimulation—tumor cells produce ligand, which activates receptors. C225 blocks by binding to the receptor with higher affinity than the ligands but does not activate the receptor. (B) Receptor overexpression—gene amplification results in vast overexpression, which likely enables dimerization and activation without ligand. Herceptin binds to and downregulates HER2:HER2 homodimers without activation. (C) Mutation/rearrangements—the receptor is altered by truncation of the extracellular ligand-binding domain (EGFRvIII) enabling it to homodimerize or heterodimerize without ligand binding. Tyrosine kinase inhibitors bind to the ATP-binding site of the cytoplasmic domain and inhibit kinase activity.

Phase III trial of radiotherapy with or without C225. Patients with stage III or regional stage IV cancer of the oropharynx, larynx, or hypopharynx are stratified by performance status, N stage, T stage, and radiotherapy schedule then randomized to receive C225 weekly or not. Radiotherapy may be delivered daily, with concommitant boost, or twice daily.

Phase ½ trial of Iressa with radiotherapy. Patients with locally advanced, untreated head and neck cancer are treated with 250 mg Iressa daily with concurrent boost radiotherapy. If tolerated, the dose of Iressa will be escalated to 500 mg. If tolerated, cisplatin will be added to daily radiotherapy with 250 mg Iressa daily. If tolerated, Iressa will be increased to 500 mg daily. Finally, Iressa at the maximum tolerated dose will be added to concurrent boost radiotherapy with cisplatin.

Trials of Herceptin plus RT. (A) Patients with locally advanced breast cancer with HER2 overexpressing residual disease after neoadjuvamt chemotherapy are treated with preoperative RT and Herceptin followed by surgery. (B) Patients with locally advanced adenocarcinoma of the esophagus are treated with weekly cisplatin/Taxol (Bristol-Meyers, United Kingdom) during RT with weekly Herceptin escalated to full dose.

Potential mechanisms of radioresistance/radiosensitization. IR-induced JNK activation promotes apoptosis, but MAPK activation by HERs dampens JNK activation and sends proliferative signals. PI3-K/Akt activation by HERs promotes survival. Inhibition of HER signals by inhibitors reduces the negative effect of MAPK on JNK, induces cell cycle arrest, and impedes repair processes.