Ba/F3 细胞系统在探索肺癌靶向治疗耐药机制中的应用,Cancer Science

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Ba/F3 细胞系统在探索肺癌靶向治疗耐药机制中的应用
Cancer Science ( IF 4.5 ) Pub Date : 2022-01-07 , DOI: 10.1111/cas.15263
Takamasa Koga ₁ , Kenichi Suda ₁ , Tetsuya Mitsudomi ₁

Affiliation

分子靶向治疗是具有驱动基因突变的转移性非小细胞肺癌 (NSCLC) 一线治疗的标准治疗。然而，尽管最初的反应很激烈，但后天抵抗的出现是不可避免的。在靶基因中获得二次突变（在靶抗性）是抗性的主要机制之一。小鼠 pro-B 细胞系 Ba/F3 的生存和增殖依赖于白细胞介素 3。在转导驱动基因后，Ba/F3 细胞变得独立于白细胞介素 3，但依赖于转导的驱动基因。因此，Ba/F3 细胞系一直是一种流行的系统，可以生成具有癌基因依赖性和易受特定靶向治疗影响的模型。这些模型已被用于估计驱动突变的致癌性或分子靶向药物的功效。此外，Ba/F3 模型以及 N-乙基-N-亚硝基脲诱变已用于衍生获得性抗性细胞以研究靶向抗性机制。在这里，我们回顾了使用 Ba/F3 模型的研究EGFR突变、ALK/ROS1/NTRK/RET融合、MET外显子 14 跳跃突变或KRAS G12C 突变以研究二级/三级耐药突变。我们确定在 Ba/F3 模型中也发现了在临床病例中可重复检测到的 68% 的耐药突变。此外，使用 Ba/F3 模型生成的敏感性数据与每种药物的临床反应密切相关。Ba/F3模型可用于全面识别诱导分子靶向药物耐药的潜在突变，并探索克服耐药性的药物。

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Utility of the Ba/F3 cell system for exploring on-target mechanisms of resistance to targeted therapies for lung cancer

Molecular targeted therapies are the standard of care for front-line treatment of metastatic non-small-cell lung cancers (NSCLCs) harboring driver gene mutations. However, despite the initial dramatic responses, the emergence of acquired resistance is inevitable. Acquisition of secondary mutations in the target gene (on-target resistance) is one of the major mechanisms of resistance. The mouse pro-B cell line Ba/F3 is dependent on interleukin-3 for survival and proliferation. Upon transduction of a driver gene, Ba/F3 cells become independent of interleukin-3 but dependent on the transduced driver gene. Therefore, the Ba/F3 cell line has been a popular system to generate models with oncogene dependence and vulnerability to specific targeted therapies. These models have been used to estimate oncogenicity of driver mutations or efficacies of molecularly targeted drugs. In addition, Ba/F3 models, together with N-ethyl-N-nitrosourea mutagenesis, have been used to derive acquired resistant cells to investigate on-target resistance mechanisms. Here, we reviewed studies that used Ba/F3 models with EGFR mutations, ALK/ROS1/NTRK/RET fusions, MET exon 14 skipping mutations, or KRAS G12C mutations to investigate secondary/tertiary drug resistant mutations. We determined that 68% of resistance mutations reproducibly detected in clinical cases were also found in Ba/F3 models. In addition, sensitivity data generated with Ba/F3 models correlated well with clinical responses to each drug. Ba/F3 models are useful to comprehensively identify potential mutations that induce resistance to molecularly targeted drugs and to explore drugs to overcome the resistance.

更新日期：2022-01-07

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