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.

Keywords: Chemoradiation; Combined modality therapy; EGFR; Epidermal growth factor receptor; Personalized medicine; Radiation.

Figure 1

Scheduling of EGFR targeted therapies with chemoradiation. EGFR inhibitors interact with radiation therapy through attenuation of DNA repair, inhibition of radiation induced pro-survival signaling pathways such as PI3k/AKT and MAPK/ERK, and by blocking tumor repopulation in between radiation fractions (Nyati et al., 2006, Chen et al., 2007, Huang et al., 2000). Top panel, treatment schedule used in RTOG 0522 (Ang et al., 2014). Shown are the concentrations of cetuximab (green) and cisplatin (red) as a function of time over the first 4 weeks of treatment. The loading dose of cetuximab theoretically antagonizes the effect of cisplatin (Morelli et al., 2005) and the long half-life of cetuximab potentially blocks redistribution of tumor cells to a more radiosensitive phase of the cell cycle (Peng et al., 1996, Di Gennaro et al., 2003). Additionally, compensatory heterodimerization of EGFR with another tyrosine kinase (e.g. c-Met, her2) can occur. Middle panel, by eliminating the loading dose of cetuximab the antagonistic effect of EGFR inhibition preceding cisplatin is mitigated. Bottom panel, by using a novel EGFR targeted agent that degrades rather than inhibits EGFR with a short half-life (6 hours) dosed daily after radiation, the negative effects of EGFR inhibition on cell cycle distribution can further be diminished while preserving the beneficial effects of these drugs.