Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea.
Department of Biomedical Science, The Graduate School, CHA University, Seongnam 13496, Korea.
Genes (Basel). 2021 Jan 25;12(2):159. doi: 10.3390/genes12020159.
Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Here, we screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Palbociclib-resistant cells were generated by exposing hormone receptor-positive breast cancer cell lines to palbociclib. Whole-exome sequencing (WES) and a mRNA microarray were performed to compare the genomic and transcriptomic landscape between both palbociclib-sensitive and resistant cells. Microarray analysis revealed 651 differentially expressed genes (DEGs), while WES revealed 107 clinically significant mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation in palbociclib-resistant cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in , and genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. In conclusion, our genomics and transcriptomics analysis using preclinical model, revealed that deregulated immune pathway is an additional mechanism of CDK4/6 inhibitor resistance besides the activation of cyclin E-CDK2 pathway and loss of RB, etc. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.
最近，细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂已广泛用于治疗晚期激素受体阳性乳腺癌。尽管临床疗效显著，但几乎所有患者最终都会对 CDK4/6 抑制剂产生耐药性。在这里，我们通过基因组学和转录组学在临床前乳腺癌模型中筛选与 palbociclib 耐药相关的基因。通过将激素受体阳性乳腺癌细胞系暴露于 palbociclib 来产生 palbociclib 耐药细胞。进行全外显子组测序（WES）和 mRNA 微阵列分析，以比较 palbociclib 敏感和耐药细胞的基因组和转录组图谱。微阵列分析显示 651 个差异表达基因（DEGs），而 WES 显示 107 个具有临床意义的突变基因。此外，对 DEGs 和突变基因的通路分析显示，palbociclib 耐药细胞中免疫通路失调。值得注意的是，DEG 注释显示 palbociclib 耐药细胞中 I 型干扰素通路的激活、免疫检查点抑制通路的激活和免疫检查点刺激通路的抑制。此外，在 palbociclib 耐药细胞中发现的 和 基因的突变被注释为与免疫通路相关。总之，我们使用临床前模型进行的基因组学和转录组学分析表明，除了 cyclin E-CDK2 通路的激活和 RB 等的缺失之外，失调的免疫通路是 CDK4/6 抑制剂耐药的另一种机制。需要进一步的研究来评估免疫通路是否可能成为克服 CDK4/6 抑制剂耐药的治疗靶点。
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