EGFR mutations compromise hypoxia-associated radiation resistance through impaired replication fork–associated DNA damage repair

Mohammad Saki, Haruhiko Makino, Prashanthi Javvadi, Nozomi Tomimatsu, Liang Hao Ding, Jennifer E. Clark, Elaine Gavin, Kenichi Takeda, Joel Andrews, Debabrata Saha, Michael D. Story, Sandeep Burma, Chaitanya S. Nirodi

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

EGFR signaling has been implicated in hypoxia-associated resistance to radiation or chemotherapy. Non–small cell lung carcinomas (NSCLC) with activating L858R or DE746-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 downregulated RAD50, a critical component of nonhomologous end joining and homologous recombination DNA repair pathways. NSCLCs and HBEC with MT-EGFR revealed elevated basal and hypoxia-induced g-H2AX–associated DNA lesions that were coincident with replication protein A in the 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.

Original languageEnglish (US)
Pages (from-to)1503-1516
Number of pages14
JournalMolecular Cancer Research
Volume15
Issue number11
DOIs
StatePublished - Nov 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Saki, M., Makino, H., Javvadi, P., Tomimatsu, N., Ding, L. H., Clark, J. E., Gavin, E., Takeda, K., Andrews, J., Saha, D., Story, M. D., Burma, S., & Nirodi, C. S. (2017). EGFR mutations compromise hypoxia-associated radiation resistance through impaired replication fork–associated DNA damage repair. Molecular Cancer Research, 15(11), 1503-1516. https://doi.org/10.1158/1541-7786.MCR-17-0136