Jernström Sandra, Hongisto Vesa, Leivonen Suvi-Katri, Due Eldri Undlien, Tadele Dagim Shiferaw, Edgren Henrik, Kallioniemi Olli, Perälä Merja, Mælandsmo Gunhild Mari, Sahlberg Kristine Kleivi
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital; KG Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
Misvik Biology Oy, Turku.
Breast Cancer (Dove Med Press). 2017 Mar 21;9:185-198. doi: 10.2147/BCTT.S115600. eCollection 2017.
Approximately 15%-20% of all diagnosed breast cancers are characterized by amplified and overexpressed HER2 (= ErbB2). These breast cancers are aggressive and have a poor prognosis. Although improvements in treatment have been achieved after the introduction of trastuzumab and lapatinib, many patients do not benefit from these drugs. Therefore, in-depth understanding of the mechanisms behind the treatment responses is essential to find alternative therapeutic strategies.
Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2-signaling pathway, and molecular mechanisms related to treatment sensitivity were sought. Cell viability was measured, and treatment responses between the cell lines were compared. To search for response predictors and genomic and transcriptomic profiling, mutations and status were explored and molecular features associated with drug sensitivity sought.
The cell lines were divided into three groups according to the growth-retarding effect induced by trastuzumab and lapatinib. Interestingly, two cell lines insensitive to trastuzumab (KPL4 and SUM190PT) showed sensitivity to an Akt1/2 kinase inhibitor. These cell lines had mutation in and loss of , suggesting an activated and druggable Akt-signaling pathway. Expression levels of five genes (, , , , and ) were suggested as predictors for the Akt1/2 kinase-inhibitor response.
Targeting the Akt-signaling pathway shows promise in cell lines that do not respond to trastuzumab. In addition, our results indicate that several molecular features determine the growth-retarding effects induced by the drugs, suggesting that parameters other than HER2 amplification/expression should be included as markers for therapy decisions.
在所有确诊的乳腺癌中，约15%-20%的特征是HER2（= ErbB2）基因扩增和过表达。这些乳腺癌具有侵袭性，预后较差。尽管引入曲妥珠单抗和拉帕替尼后治疗取得了进展，但许多患者并未从这些药物中获益。因此，深入了解治疗反应背后的机制对于寻找替代治疗策略至关重要。
用22种市售化合物筛选了13种HER2阳性乳腺癌细胞系，这些化合物主要靶向ErbB2信号通路中的蛋白质，并寻找与治疗敏感性相关的分子机制。测量细胞活力，并比较细胞系之间的治疗反应。为了寻找反应预测因子以及进行基因组和转录组分析，探索了基因突变和状态，并寻找与药物敏感性相关的分子特征。
根据曲妥珠单抗和拉帕替尼诱导的生长抑制作用，将细胞系分为三组。有趣的是，两种对曲妥珠单抗不敏感的细胞系（KPL4和SUM190PT）对Akt1/2激酶抑制剂敏感。这些细胞系存在基因突变且缺失，提示Akt信号通路被激活且可被药物作用。五个基因（、、、和）的表达水平被认为是Akt1/2激酶抑制剂反应的预测因子。
在对曲妥珠单抗无反应的细胞系中，靶向Akt信号通路显示出前景。此外，我们的结果表明，几种分子特征决定了药物诱导的生长抑制作用，这表明除HER2扩增/表达外的其他参数也应作为治疗决策的标志物。
