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 NCOR1, MUC4, and MUC16 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.

中文翻译：

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临床前乳腺癌模型中与Palbociclib耐药性相关的免疫通路失控：基因组学和转录组学

最近，细胞周期蛋白依赖性激酶（CDK）4/6抑制剂已被广泛用于治疗晚期激素受体阳性乳腺癌。尽管临床结果令人满意，但几乎所有患者最终都对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了与palbociclib耐药相关的基因。Palbociclib耐药细胞是通过将激素受体阳性乳腺癌细胞系暴露于palbociclib而产生的。进行了全外显子测序（WES）和mRNA微阵列，以比较palbociclib敏感细胞和耐药细胞之间的基因组和转录组情况。基因芯片分析显示651个差异表达基因（DEG），而WES显示107个临床上重要的突变基因。此外，DEG和突变基因的信号通路分析揭示了palbociclib耐药细胞中的免疫通路失调。值得注意的是，DEG注释揭示了palbociclib耐药细胞中I型干扰素途径的激活，免疫检查点抑制途径的激活以及免疫检查点刺激途径的抑制。而且，在在耐palbociclib的细胞中发现的NCOR1，MUC4和MUC16基因被注释为与免疫途径有关。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，失活的免疫途径是CDK4 / 6抑制剂耐药性的另一种机制，除了激活细胞周期蛋白E-CDK2途径和RB丢失等外，还有必要进行进一步的研究以评估是否免疫途径可能是克服CDK4 / 6抑制剂耐药性的治疗目标。