携带活化 SOS1 基因突变的 BH1406 非小细胞肺癌 (NSCLC) 细胞系的特征。

IF 4 2区 医学 Q2 ONCOLOGY Translational lung cancer research Pub Date : 2024-11-30 Epub Date: 2024-11-28 DOI:10.21037/tlcr-24-570
Gerhard Hamilton, Sandra Stickler, Mikhail Ermakov, Marie-Therese Eggerstorfer, Francesca Paola Nocera, Martin Hohenegger, Lukas Weigl, Maximilian Johannes Hochmair, Karl Kashofer
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引用次数: 0

摘要

背景:大约30%没有可识别的致癌驱动突变的非小细胞肺癌(NSCLC)患者不适合靶向治疗。肿瘤细胞的功能药物筛选有助于识别基因面板无法识别的敏感药物靶点,用于靶向突变分析。本研究的目的是表征携带激活SOS1突变的BH1406细胞系,并检查其对同源抑制剂的敏感性。方法:从胸腔积液中建立非小细胞肺癌细胞系BH1406,在初始活力筛选中发现对SOS1抑制剂BAY-293敏感。由于在有限的下一代测序(NGS)肺癌突变面板中没有检测到驱动因素,因此患者接受了化疗,结果不佳。该细胞系进一步通过外显子组测序、SOS1 Western blotting、二维(2D)和三维(3D)化学敏感性比较和磷酸化蛋白阵列进行表征。结果:在全外显子组测序(WES)中,检测到位于已知P478L激活突变附近的SOS1突变P481delinsLFFL。除BAY-293外,BH1406细胞还对SOS1抑制剂MRTX0902和BI-3406敏感。与2D培养相比,BH1406细胞在3D条件下对BI-3406的敏感性增加。Western blot磷酸化蛋白阵列显示BAY-293在2D培养中降低BH1406中CREB、GSK3、CHK-2和STAT3的磷酸化水平。在3D条件下,细胞从GSK3α切换到升高的ERK1/2信号,再次被SOS1抑制剂BAY-293阻断。SOS1抑制剂MRTX0902和BI3406也获得了类似的结果。此外,PI3K抑制剂dactolisib、GSK-3抑制剂BI-5521以及bromodomain蛋白导向的PROTAC ARV-771均能显著抑制BH1406细胞的生长,并与BAY-293表现出协同作用。此外,Western blot结果显示,BAY-293治疗后SOS1和MYC蛋白的表达降低。结论:肺癌中罕见的SOS1 P481delinsLFFL突变可能与相应的抑制剂靶向,单独或联合GSK3/PI3K/BET抑制剂。BH1406细胞是一种适合SOS1药物性分子表征的新型细胞模型。这种罕见的致癌驱动基因不包括在标准的NGS面板中,需要通过像WES这样的扩展试验来检测。
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Characterization of the BH1406 non-small cell lung cancer (NSCLC) cell line carrying an activating SOS1 mutation.

Background: Approximately 30% of the non-small cell lung cancer (NSCLC) patients which harbor no recognizable oncogenic driver mutation are not eligible for targeted therapy. Functional drug screening of tumor cells helps to identify susceptible drug targets not recognized by gene panels for targeted mutation analysis. The aim of this study is to characterize the BH1406 cell line carrying an activating SOS1 mutation and to check its sensitivity to cognate inhibitors.

Methods: The NSCLC cell line BH1406 was established from a pleural effusion and found to be sensitive to the SOS1 inhibitor BAY-293 in initial viability screenings. Since in a limited next-generation sequencing (NGS) lung cancer mutation panel no driver could be detected, the patient underwent chemotherapy with poor outcome. This cell line was further characterized by exome sequencing, SOS1 Western blotting, comparison of two-dimensional (2D) and three-dimensional (3D) chemosensitivity assays and phosphoprotein arrays.

Results: In whole-exome sequencing (WES) the SOS1 mutation P481delinsLFFL, positioned near the known P478L activating mutation was detected. Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406. The sensitivity of BH1406 cells to BI-3406 was increased under 3D conditions compared to 2D cultures. Western blot phosphoprotein arrays revealed reduced phosphorylation of CREB, GSK3, CHK-2 and STAT3 in BH1406 by BAY-293 treatment in 2D culture. In 3D conditions, cells switched from GSK3α to elevated ERK1/2 signaling, again blocked by the SOS1 inhibitor BAY-293. Similar results were obtained for the SOS1 inhibitors MRTX0902 and BI3406. Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293. Furthermore, Western blots demonstrated reduced expression of SOS1 and MYC proteins in response to BAY-293 treatment.

Conclusions: The rare SOS1 P481delinsLFFL mutation in lung cancer may be targetable with corresponding inhibitors, alone or in combination with GSK3/PI3K/BET inhibitors. BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES.

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来源期刊
CiteScore
7.20
自引率
2.50%
发文量
137
期刊介绍: Translational Lung Cancer Research(TLCR, Transl Lung Cancer Res, Print ISSN 2218-6751; Online ISSN 2226-4477) is an international, peer-reviewed, open-access journal, which was founded in March 2012. TLCR is indexed by PubMed/PubMed Central and the Chemical Abstracts Service (CAS) Databases. It is published quarterly the first year, and published bimonthly since February 2013. It provides practical up-to-date information on prevention, early detection, diagnosis, and treatment of lung cancer. Specific areas of its interest include, but not limited to, multimodality therapy, markers, imaging, tumor biology, pathology, chemoprevention, and technical advances related to lung cancer.
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