EGFR Mutations Compromise Hypoxia-Associated Radiation Resistance through Impaired Replication Fork–Associated DNA Damage Repair

Abstract

Epidermal growth factor receptor (EGFR) signaling has been implicated in hypoxia-associated resistance to radiation or chemotherapy. Non-small cell lung carcinomas (NSCLC) with activating L858R or ΔE746–E750 EGFR mutations exhibit elevated EGFR activity and downstream signaling. Here, relative to wild type (WT) EGFR, mutant (MT) EGFR expression significantly increases radiosensitivity in hypoxic cells. Gene expression profiling in human bronchial epithelial cells (HBEC) revealed that MT-EGFR expression elevated transcripts related to cell cycle and replication in aerobic and hypoxic conditions and down-regulated RAD50, a critical component of non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways. NSCLCs and HBEC with MT-EGFR revealed elevated basal and hypoxia-induced γ-H2AX-associated DNA lesions that were coincident with replication protein A in S-phase nuclei. DNA fiber analysis showed that, relative to WT-EGFR, MT-EGFR NSCLCs harbored significantly higher levels of stalled replication forks and decreased fork velocities in aerobic and hypoxic conditions. EGFR blockade by cetuximab significantly increased radiosensitivity in hypoxic cells, recapitulating MT-EGFR expression and closely resembling synthetic lethality of PARP inhibition.

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

“…Glioma accounts for 46% of all primary intracranial tumors in the central nervous system . Increasing evidence has suggested that rapid acquired therapeutic resistance is the major cause of the failure of standard comprehensive treatments, leading to the recurrence and high mortality of glioma . Various molecular pathways have been shown to be responsible for the acquisition of therapeutic resistance in glioma .…”

“…28 Increasing evidence has suggested that rapid acquired therapeutic resistance is the major cause of the failure of standard comprehensive treatments, leading to the recurrence and high mortality of glioma. 29,30 Various molecular pathways have been shown to be responsible for the acquisition of therapeutic resistance in glioma. 26,[31][32][33] Therefore, it is essential to identify the mechanisms, especially prognostic biomarkers, underlying therapeutic resistance in glioma.…”

Inside the hypoxic tumour: reprogramming of the DDR and radioresistance

“…Interestingly, all components of the MRN were found to be downregulated both at the mRNA and protein level in NSCLCs harbouring EGFR mutations incubated in severe hypoxia (0.1% O 2 ). This downregulation in EGFR-mutated cells correlated with their increased sensitivity to EGFR-inhibiting drugs 71 .…”

Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

“…EGFR nuclear translocation is stimulated by radiation mediated by Cavelolin-1 (CAV-1), and CAV-1 knockdown radiosensitizes triple-negative breast cancer, a tumor type for which there are no current targeted therapies and poor prognoses [189] . Mutant forms of EGFR (D746-750, L858R, and the targeted-therapy resistant T790M mutant) confer radiosensitivity to hypoxic lung cancer cells, at least in part due to downregulation of RAD50, a member of the MRE11/RAD50/NBS1 complex that plays early end-processing and signaling roles in NHEJ and HR [190] . These results suggest that tumor EGFR status can be used to personalize radiotherapy treatment plans and augmentation with NHEJ inhibitors.…”