Abstract 17P
Background
Esophageal adenocarcinoma (EAC) is a lethal cancer type rapidly increasing worldwide. Overexpression of the human epidermal growth factor receptor 2 (HER2) occurs in approximately one third of patients. However, small-molecule tyrosine kinase inhibitors, like lapatinib, show limited clinical benefits due to fast-developed drug unresponsiveness. The evolutionary driver of resistance remains largely unknown.
Methods
We generated reversible drug-tolerant persister and stable resistant cell lines through short- and long-term drug exposure. Time-course matched ATAC-seq and RNA-seq analysis were performed to dynamically decipher drivers for resistance development. Functional validation in vitro and in vivo using genetic and pharmacological approaches was conducted in both drug-sensitive and resistant cells. Furthermore, we detected the metabolic spectrum via flow cytometry and compared metabolic vulnerability through pharmacological disruption of critical enzymes involved between sensitive and resistant cells.
Results
Integrated multi-omics analysis revealed a high degree of NRF2 dependency during resistance acquisition. Inhibition of NRF2 incapacitated drug-tolerant persister development, and both naturally occurring and developed resistant cell lines showed consistent vulnerability to NRF2 inhibition. Conversely, NRF2 overexpression/activation promoted survival of sensitive cell lines from lapatinib toxicity by reprogramming metabolism to glutathione. Glutathione precursor supplementation rescued sensitive cells from lapatinib treatment, while disrupting the glutathione-conversion enzyme, GPX4, rapidly triggered cell death in resistant cell lines. In vivo, NRF2 inhibitor substantially suppressed the growth of lapatinib-resistant EAC xenografts, but tumor growth persisted in lapatinib-sensitive EAC-bearing mice, confirming the NRF2 vulnerability.
Conclusions
NRF2 is essential for acquiring resistance to ERBB2 inhibition, and it promotes a switch to glutathione dependency. These results offer a promising opportunity to tackle cellular adaptation and ensuing drug resistance in incurable EAC.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
Wellcome Trust.
Disclosure
All authors have declared no conflicts of interest.
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