DOI: 10.1101/513994Jan 8, 2019Paper

NRF2-dependent metabolic reprogramming is required for tumor recurrence following oncogene inhibition

BioRxiv : the Preprint Server for Biology
Douglas B FoxJames V Alvarez

Abstract

Oncogenic signaling pathways both directly and indirectly regulate anabolic metabolism, and this is required for tumor growth. Targeted therapies that inhibit oncogenic signaling have dramatic impacts on cellular metabolism. However, it is not known whether the acquisition of resistance to these therapies is associated with - or driven by - alterations in cellular metabolism. To address this, we used a conditional mouse model of Her2-driven breast cancer to study metabolic adaptations following Her2 inhibition, during residual disease, and after tumor recurrence. We found that Her2 downregulation caused widespread changes in cellular metabolism, culminating in oxidative stress. Tumor cells adapted to this metabolic stress by upregulation of the antioxidant transcription factor, NRF2. Constitutive NRF2 expression persisted during residual disease and tumor recurrence, and NRF2 was both sufficient to promote tumor recurrence, and necessary for recurrent tumor growth. These results are supported by clinical data showing that the NRF2 transcriptional program is activated in recurrent breast tumors, and that NRF2 is associated with poor prognosis in patients with breast cancer. Mechanistically, NRF2 signaling in recurrent tumors ind...Continue Reading

Related Concepts

Base Sequence
Malignant Neoplasm of Breast
Carcinogens
Down-Regulation
Glutaminase
Metabolic Inhibition
Signal Pathways
Transcription Factor
Transcription, Genetic
Up-Regulation (Physiology)

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