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

Producción científica: Articlerevisión exhaustiva

8 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)1503-1516
Número de páginas14
PublicaciónMolecular Cancer Research
Volumen15
N.º11
DOI
EstadoPublished - nov 2017
Publicado de forma externa

ASJC Scopus subject areas

  • General Medicine

Huella

Profundice en los temas de investigación de 'EGFR mutations compromise hypoxia-associated radiation resistance through impaired replication fork–associated DNA damage repair'. En conjunto forman una huella única.

Citar esto