Despite its efficacy in solid tumours, in particular HER2⁺ breast cancer, HER2‐targeted therapy has given rise to disappointing results in non‐small cell lung cancer (NSCLC). With the aim of refining the target population for anti‐HER2 therapies in NSCLC, we investigated the relationships between HER2 and the tumour suppressor fragile histidine triad (FHIT) in lung tumour cells. First, we observed a negative correlation between FHIT expression and the activated form of HER2 (pHER2) in NSCLC samples and in lung tumour cell lines. Moreover, the silencing or overexpression of FHIT in lung cell lines led to an increase or decrease of HER2 activity, respectively. We also demonstrated that two anti‐HER2 drugs, irbinitinib and trastuzumab, restore a more epithelial phenotype and counteract cell invasiveness and growth of FHIT‐silenced tumour cell lines. Finally, we showed that the FHIT^low/pHER2^high phenotype predicts sensitivity to an anti‐HER2 therapy in primary tumour cells from NSCLC patients. Our results show that FHIT regulates the activity of HER2 in lung tumour cells and that FHIT‐inactivated tumour cells are sensitive to HER2 inhibitors. A new subclass of patients with NSCLC may be eligible for an anti‐HER2 therapy. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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非小细胞肺癌中的FHITlow / pHER2high标记可预测抗HER2分子的疗效。

尽管它对实体瘤有效，尤其是HER2 ⁺乳腺癌，HER2靶向治疗在非小细胞肺癌（NSCLC）中的效果令人失望。为了完善NSCLC中抗HER2治疗的目标人群，我们研究了HER2与肺肿瘤细胞中的肿瘤抑制物脆弱组氨酸三联体（FHIT）之间的关系。首先，我们在NSCLC样本和肺肿瘤细胞系中观察到FHIT表达与HER2活化形式（pHER2）之间的负相关。此外，肺细胞系中FHIT的沉默或过表达分别导致HER2活性的升高或降低。我们还证明了两种抗HER2药物irbinitinib和曲妥珠单抗可恢复更上皮的表型，并抵消FHIT沉默的肿瘤细胞系的细胞侵袭和生长。最后，我们证明了FHIT^低/ pHER2^高表型可预测NSCLC患者原发性肿瘤细胞对抗HER2治疗的敏感性。我们的结果表明，FHIT调节肺肿瘤细胞中HER2的活性，而FHIT灭活的肿瘤细胞对HER2抑制剂敏感。NSCLC患者的新亚类可能符合抗HER2治疗的条件。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版