Hirai Noriko, Hatanaka Yutaka, Hatanaka Kanako C, Uno Yuji, Chiba Shin-Ichi, Umekage Yasuhiro, Minami Yoshinori, Okumura Shunsuke, Ohsaki Yoshinobu, Sasaki Takaaki
Respiratory Center, Asahikawa Medical University Hospital, Asahikawa, Japan.
Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan.
Transl Lung Cancer Res. 2021 Sep;10(9):3737-3744. doi: 10.21037/tlcr-21-415.
Combination therapy with the B-Raf inhibitor, dabrafenib, and the MEK inhibitor, trametinib (DT) is commonly used to treat patients with B-Raf proto-oncogene, serine/threonine kinase V600E ( V600E)-mutated non-small cell lung cancer (NSCLC). However, the mechanisms through which cancer develops DT resistance are unclear. Here, we investigated new mechanisms underlying acquired DT-resistant NSCLC with the V600E mutation.
We compared genomic signatures before and after DT treatment in patients with NSCLC.
Two of four patients treated with DT developed carcinomatous pleuritis within 3 months. Target DNA sequencing and quantitative polymerase chain reaction (PCR) analyses revealed the increased expression level of cyclin-dependent kinase 4 (). We also found prominent protein expression of after DT treatment. Induction of expression in a cell line derived from a patient with the V600E mutation resulted in partial resistance to dabrafenib.
Our findings suggest a possible relationship between upregulation and acquired resistance to DT therapy.
B-Raf抑制剂达拉非尼和MEK抑制剂曲美替尼（DT）联合治疗常用于治疗B-Raf原癌基因、丝氨酸/苏氨酸激酶V600E（V600E）突变的非小细胞肺癌（NSCLC）患者。然而，癌症产生DT耐药性的机制尚不清楚。在此，我们研究了携带V600E突变的获得性DT耐药NSCLC的新机制。
我们比较了NSCLC患者DT治疗前后的基因组特征。
接受DT治疗的4例患者中有2例在3个月内发生癌性胸膜炎。靶向DNA测序和定量聚合酶链反应（PCR）分析显示细胞周期蛋白依赖性激酶4（）的表达水平增加。我们还发现DT治疗后蛋白表达显著。在源自V600E突变患者的细胞系中诱导表达导致对达拉非尼产生部分耐药性。
我们的研究结果表明上调与获得性DT治疗耐药之间可能存在关联。
