Synthetic lethality of EGFR blockade in the context of tumor hypoxia.

Abstract

10624 Background: Hypoxia induces a wide spectrum of biological responses in tumors that alter tumor radio-sensitivity. In several tumors, including non-small cell lung carcinoma (NSCLC), the epidermal growth factor receptor (EGFR) is frequently over-expressed and activated in response to hypoxia, although the precise role of EGFR in hypoxia-associated radioresitance is unclear. Activating mutations in EGFR have been clinically linked to dramatic responses to EGFR tyrosine kinase inhibitors. We previously demonstrated that NSCLCs harboring activating EGFR mutations are radiosensitive with severe deficits in the non homologous end-joining (NHEJ) repair of DNA damage. Methods: We investigated hypoxia associated radiation responses in a panel of NSCLC cell lines and immortalized human bronchial epithelial cells expressing wild type EGFR (WT) or expressed EGFR forms with somatic activating L858R or DE746-E750 mutations (MT). Results: (1) Relative to WT EGFR, MT EGFR expression is associated with significantly higher radiosensitivity under chronic hypoxia (2) Under hypoxic conditions, MT EGFR expression is associated with a unique spectrum of DNA damage responses (DDR) that significantly deviated from canonical response of WT EGFR expressing NSCLCs (3) Genome wide gene expression analysis identified a dramatic hypoxia-associated DDR shift to selective down-regulation of homologous recombination (HR). Moreover, MT EGFR deficits in NHEJ caused a synthetic lethality effect in the context of hypoxia through a simultaneous blockade of HR and NHEJ. (4) Blockade of WT EGFR by the anti-EGFR monoclonal antibody, cetuximab perfectly recapitulated the contextual synthetic lethality of MT EGFR expression. (5) Cetuximab had a dramatic synergistic effect on survival of rat lung orthotopic tumors where hypo-fractionated radiotherapy or cetuximab alone had marginally controlled tumors. Conclusions: The data support a critical role for EGFR-mediated DNA repair in hypoxia associated tumor radio-resistance. Furthermore, this role could be a target for refractory hypoxic EGFR-WT tumor especially in the context of hypo-fractionated radiotherapy which, in its current form, is potentially counter-productive for hypoxic tumors.