EGFR-mediated chromatin condensation protects KRAS-mutant cancer cells against ionizing radiation

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Epidermal growth factor receptor (EGFR) inhibitors can potentiate the effects of ionizing radiation (IR).
• Predictive biomarkers for EGFR inhibitor-induced radiosensitization in cancer remain largely undiscovered.
• Non-small cell lung cancer (NSCLC) with KRAS mutations often shows resistance to EGFR-targeted therapies.

Purpose of the Study:

• To identify genomic biomarkers predicting radiosensitization by EGFR inhibitors.
• To elucidate the molecular mechanisms underlying radiosensitization in KRAS-mutant NSCLC.
• To explore novel therapeutic strategies combining EGFR inhibitors with DNA-damaging agents.

Main Methods:

• Screening of 40 non-small cell lung cancer (NSCLC) cell lines to identify correlations between mutations and radiosensitization.
• Investigating the role of EGFR signaling in chromatin condensation and DNA double-strand break (DSB) formation in response to IR.
• Analyzing the involvement of histone modifications (H3S10ph, H3K9me3), Aurora B, protein kinase C alpha (PKCα), and MEK/ERK signaling pathways.
• Assessing the impact of autophagy blockade on cell fate (senescence vs. apoptosis) in response to IR and erlotinib.

Main Results:

• A positive correlation was found between KRAS mutations and radiosensitization by EGFR inhibitors (erlotinib, cetuximab) in NSCLC cell lines.
• EGFR signaling in KRAS-mutant NSCLC promotes interphase chromatin condensation, limiting IR-induced DSBs.
• This condensation involves a mitosis-like histone modification pattern regulated by Aurora B, EGFR, and PKCα.
• EGFR signaling, via PKCα and MEK/ERK, suppresses premature senescence induced by DSBs.
• Autophagy inhibition triggers a KRAS-dependent switch from senescence to apoptosis when combined with IR and erlotinib.

Conclusions:

• EGFR inhibition can overcome a novel radioresistance mechanism in KRAS-mutant NSCLC driven by chromatin condensation.
• This finding contrasts with the general unresponsiveness of KRAS-mutant cancers to EGFR inhibitors as monotherapy.
• EGFR-targeted agents may be repositioned for combination therapy with DNA-damaging agents in KRAS-mutant NSCLC.