The intriguing interplay between therapies targeting the epidermal growth factor receptor, the hypoxic microenvironment and hypoxia-inducible factors.

Despite their individual key roles in promoting cancer progression and treatment resistance, our knowledge about the impact of tumor hypoxia on the activity of the epidermal growth factor receptor (EGFR) pathway in cancer and vice versa remains limited. Preclinical and clinical studies support an important link between hypoxia and upregulation of EGFR in cancers that do not display genetic alterations of the receptor. Subsequent EGFR signaling stimulates hypoxia-inducible factor (HIF) signaling and thus augments induction of proteins that promote cellular survival in a hostile microenvironment. Considering the effects of EGFR-targeting agents under reduced oxygen conditions, it is now accepted that, together with their demonstrated antiproliferative and proapoptotic effects, the antiangiogenic activity of these drugs also contributes to their overall antitumor activity in vivo. Treatment of human tumor cells with EGFR inhibitors leads to decreased HIF-1α and VEGF secretion by tumor cells, resulting in vascular normalization, improved blood flow and thus improved oxygenation. These findings may have major implications with respect to the efficacy of both radiotherapy and subsequent chemotherapy when combined with EGFR inhibitors. A major challenge remains to assess which sequence of these drugs with radiation or chemotherapy is optimal. Moreover, recent data suggest that the lack of clinical responses to EGFR-directed therapy may be circumvented by supplementation of the anti-EGFR therapy with additional approaches targeting HIF-1α or VEGF. Further studies thus are warranted to define the precise mechanistic and therapeutic implications of the hypoxic response relative to the EGFR signaling pathway in cancer.