Zhang Wei, Lang Jiaqing, Chattrakarn Sorayut, Wong Chun Wai, Li Shiyang, Kan Karmern, Liu Hongcai, Gu Wenchao, Zhang Jingwei, Westermarck Jukka, Whitmarsh Alan J, Sharrocks Andrew D, Tournier Cathy
Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health (FBMH), University of Manchester, Manchester, UK.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
Oncogene. 2025 Jun 5. doi: 10.1038/s41388-025-03459-0.
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.
人表皮生长因子受体2（HER2，也称为ERBB2）是食管腺癌（OAC）中一种常见的过表达癌蛋白。尽管如此，HER2阻断剂未能显著改善OAC患者的预后，尽管其在乳腺癌中取得了显著的临床成功。为了解决这一难题，我们研究了靶向HER2时耐药性是如何逐渐出现的。我们发现，能够在双重HER1/HER2酪氨酸激酶抑制剂拉帕替尼存在的情况下存活的OAC细胞系中，核因子红细胞2相关因子2（NRF2）的蛋白水平显著增加。事实上，敲低NRF2增强了拉帕替尼的细胞毒性作用，而OAC细胞中NRF2表达的增加降低了它们对HER抑制的敏感性。此外，NRF2的长期过表达使OAC细胞系对NRF2的生长依赖性越来越强。进一步分析表明，与拉帕替尼诱导的持续和耐药表型相关的NRF2介导的转录激活与随后谷胱甘肽代谢的增加同时发生。重要的是，对拉帕替尼耐药的OAC异种移植物对NRF2途径的药理学抑制变得极其敏感。总之，这些发现突出了一种有前景的治疗策略，即通过靶向NRF2途径并结合受体酪氨酸激酶抑制来治疗难治性OAC。
