EGFR targeted therapies and radiation: Optimizing efficacy by appropriate drug scheduling and patient selection

Abstract

The epidermal growth factor receptor (EGFR) plays an important role in tumor progression and treatment resistance for many types of malignancies including head and neck, colorectal, and nonsmall cell lung cancer. Several EGFR targeted therapies are efficacious as single agents or in combination with chemotherapy. Given the toxicity associated with chemoradiation and poor outcomes seen in several types of cancers, combinations of EGFR targeted agents with or without chemotherapy have been tested in patients receiving radiation. To date, the only FDA approved use of an anti-EGFR therapy in combination with radiation therapy is for locally advanced head and neck cancer. Given the important role EGFR plays in lung and colorectal cancer and the benefit of EGFR inhibition combined with chemotherapy in these disease sites, it is perplexing why EGFR targeted therapies in combination with radiation or chemoradiation have not been more successful. In this review we summarize the clinical findings of EGFR targeted therapies combined with radiation and chemoradiation regimens. We then discuss the interaction between EGFR and radiation including radiation induced EGFR signaling, the effect of EGFR on DNA damage repair, and potential mechanisms of radiosensitization. Finally, we examine the potential pitfalls with scheduling EGFR targeted therapies with chemoradiation and the use of predictive biomarkers to improve patient selection.

Enhanced efficacy of AZD3759 and radiation on brain metastasis from EGFR mutant non‐small cell lung cancer

“…Besides, we also detected the detailed mechanisms for inhibiting effect of EGFR‐TKIs on DNA damage repair. The results of our data showed that combined AZD3759 with radiation significantly prolonged the presence of DNA DSBs compared to radiation alone, this is in line with previous studies . Moreover, the results of western blot and co‐IP showed that in response to radiation, there was radiation dose‐dependently decrease in rad51 expression and dose‐dependently increase in binding between DNA‐PKcs and EGFR in nucleus.…”

A retrospective paired study: efficacy and toxicity of nimotuzumab versus cisplatin concurrent with radiotherapy in nasopharyngeal carcinoma

“…Altered EGFR signaling is widely implicated in cell apoptosis resistance, proliferation, radiotherapy resistance, metastasis and invasion [16, 17]. Targeted therapies for treatment of NPC have become a topic of increased research interest internationally due to favorable efficacy and low toxicity.…”

Radiotherapy plus EGFR inhibitors: synergistic modalities

“…In fact, the combination of EGFR blockade and radiation exploits three distinct roles that the EGFR pathway plays in cancer progression: enhanced cell proliferation, the activation of pro-survival pathways, and DNA repair [8]. What follows is a brief explanation of these functions and of the mechanisms of resistance to anti-EGFR therapies.…”

“…Radiation promotes the internalization and transport of EGFR by caveolin-1, leading to the activation of DNA-PK (a vital kinase for joining repair) in response to DNA damage. In this respect, researchers have shown that inhibition of EGFR with cetuximab attenuates EGFR nuclear import and suppresses DNA-PK activity [8].…”