NRF2-mediated persistent adaptation of oesophageal adenocarcinoma cells to HER2 inhibition

The human epidermal growth factor receptor 2 (HER2, also known as ERBB2) is a commonly over-expressed oncoprotein in oesophageal adenocarcinoma (OAC). Nonetheless, HER2-blocking agents have failed to significantly improve the outcome for OAC patients, despite achieving striking clinical success in breast cancer. To address this conundrum, we investigated how resistance progressively emerges when HER2 is targeted. We discovered that OAC cell lines that are capable of surviving in the presence of the dual HER1/HER2 tyrosine kinase inhibitor lapatinib exhibit a significant increase in the protein level of nuclear factor erythroid 2-related factor 2 (NRF2). Indeed, NRF2 knockdown enhanced the cytotoxic effect of lapatinib, while increased NRF2 expression in OAC cells reduced their sensitivity to HER inhibition. Furthermore, prolonged overexpression of NRF2 made OAC cell lines increasingly dependent on NRF2 for growth. Further analyses indicated that the activation of NRF2-mediated transcription that was associated with lapatinib-induced persistent and resistant phenotypes coincided with a subsequent increase in glutathione metabolism. Importantly, lapatinib resistant OAC xenografts become exquisitely sensitive to pharmacological inhibition of the NRF2 pathway. Together, these findings highlight a promising therapeutic strategy for treating refractory OAC by targeting the NRF2 pathway in combination with receptor tyrosine kinase inhibition.