Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors

Area of Science:

• Oncology
• Cancer Metabolism
• Epigenetics

Background:

• Metabolism and chromatin signaling interplay is crucial in cancer progression.
• Aberrant NRF2 pathway activation in lung adenocarcinoma (LUAD) drives aggressive and chemo-resistant disease.
• Mechanisms by which tumor metabolic reprogramming creates chromatin vulnerabilities are unclear.

Purpose of the Study:

• To investigate if NRF2 activation sensitizes LUAD to class I histone deacetylase (HDAC) inhibition.
• To elucidate the underlying molecular mechanisms linking NRF2, HDAC inhibition, and metabolic vulnerabilities.
• To explore the therapeutic potential of repurposing HDAC inhibitors for NRF2-active solid tumors.

Main Methods:

• Chromatin-focused CRISPR screening in LUAD cells.
• In vitro, in vivo (mouse models), and patient-derived xenograft studies.
• Integrative epigenomic, transcriptomic, and metabolomic analyses.

Main Results:

• NRF2 activation confers sensitivity to class I HDAC inhibition in LUAD.
• HDAC inhibition leads to H4ac redistribution, downregulating metabolic enzymes.
• Metabolic flux is reduced in amino acid and nucleotide synthesis pathways crucial for NRF2-active cancer cells.
• This sensitivity is consistent across cell cultures, mouse models, and xenografts.

Conclusions:

• NRF2 activation creates a metabolic dependency that can be exploited by HDAC inhibitors in LUAD.
• HDAC inhibition disrupts essential metabolic pathways, selectively impacting NRF2-active cancer cells.
• NRF2 activation may serve as a predictive biomarker for HDAC inhibitor therapy in solid tumors.