Miyashita Yosuke, Tajima Ken, Izumi Kenta, Matsumoto Naohisa, Hayakawa Daisuke, Nakamura Ikuko Takeda, Katayama Isana, Wibowo Adityo, Matsuda Hironari, Winardi Wira, Amien Bagus Radityo, Mitsuishi Yoichiro, Takahashi Fumiyuki, Nakamura Kohta, Uchibori Ken, Yanagitani Noriko, Hayashi Takuo, Takamochi Kazuya, Suzuki Kenji, Katayama Ryohei, Takahashi Kazuhisa
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Cancer Sci. 2025 May;116(5):1392-1404. doi: 10.1111/cas.70032. Epub 2025 Mar 4.
Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, is the first-line therapy for lung cancer harboring EGFR mutations. The mechanisms underlying osimertinib resistance are diverse, with approximately half remaining unknown. Epigenetic dysregulation is implicated in drug resistance; however, the mechanisms remain unclear. Therefore, we investigated epigenetic involvement in osimertinib resistance and its therapeutic potential. We established osimertinib-resistant cells and used an assay for transposase-accessible chromatin using sequencing to evaluate chromatin accessibility, finding significant changes post-resistance. Combining the assay for transposase-accessible chromatin and RNA sequencing data, we identified FGF1 as a resistance-related gene regulated by histone modifications. FGF1 induced osimertinib resistance, and its suppression attenuated resistance. Bromodomain and extra-terminal domain inhibitors combined with osimertinib overcame osimertinib resistance by reducing FGF1 expression. Increased FGF1 expression was observed in osimertinib-resistant clinical samples. This combination therapy was effective in cell lines and mouse xenograft models. These results suggest targeting histone modifications using bromodomain and extra-terminal domain inhibitors as a novel approach to overcoming osimertinib resistance.
奥希替尼是一种第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，是治疗携带EGFR突变肺癌的一线疗法。奥希替尼耐药的机制多种多样，约半数机制仍不明。表观遗传失调与耐药有关；然而，其机制仍不清楚。因此，我们研究了表观遗传在奥希替尼耐药中的作用及其治疗潜力。我们建立了奥希替尼耐药细胞系，并使用转座酶可及染色质测序分析来评估染色质可及性，发现耐药后有显著变化。结合转座酶可及染色质分析和RNA测序数据，我们确定成纤维细胞生长因子1（FGF1）是一个受组蛋白修饰调控的耐药相关基因。FGF1诱导奥希替尼耐药，抑制它可减弱耐药。含溴结构域和额外末端结构域抑制剂与奥希替尼联合使用，通过降低FGF1表达克服了奥希替尼耐药。在奥希替尼耐药的临床样本中观察到FGF1表达增加。这种联合疗法在细胞系和小鼠异种移植模型中有效。这些结果表明，使用含溴结构域和额外末端结构域抑制剂靶向组蛋白修饰是克服奥希替尼耐药的一种新方法。
