Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer.
Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer.
复制标题
干扰素信号通路的激活与ER阳性乳腺癌对CDK4/6抑制剂的耐药性和免疫检查点的激活有关。
DOI：
10.1158/1078-0432.ccr-19-4191
复制
发表时间：
2021-09-01
期刊：
影响因子：
--
通讯作者：
Schiff R
中科院分区：
文献类型：
--
作者：
De Angelis C;Fu X;Cataldo ML;Nardone A;Pereira R;Veeraraghavan J;Nanda S;Qin L;Sethunath V;Wang T;Hilsenbeck SG;Benelli M;Migliaccio I;Guarducci C;Malorni L;Litchfield LM;Liu J;Donaldson J;Selenica P;Brown DN;Weigelt B;Reis-Filho JS;Park BH;Hurvitz SA;Slamon DJ;Rimawi MF;Jansen VM;Jeselsohn R;Osborne CK;Schiff R
CDK4/6抑制剂对ER+/HER2-乳腺癌（BC）非常有效；然而，内在的和后天的抵抗是常见的。阐明 CDK4/6i 敏感性和耐药性的分子特征可能会导致预测性生物标志物和新治疗靶点的识别，从而为改善患者预后铺平道路。使用亲本 BC 细胞及其内分泌抗性衍生物 (EndoR)。对 palbociclib 具有获得性耐药性 (PalboR) 的衍生物是由亲本和雌激素剥夺耐药性 MCF7 和 T47D 细胞产生的。在 Palbociclib 敏感品系和 PalboR 品系中进行转录组学和蛋白质组学分析。对来自 CDK4/6i 新辅助试验和公开数据集的基因表达数据进行了询问，以了解基因特征与患者结果的相关性。亲本和 EndoR BC 系对哌柏西利表现出不同程度的敏感性。对这些细胞系的转录组分析发现，高干扰素 (IFN) 信号传导与 CDK4/6i 敏感性降低之间存在关联；因此得出了“干扰素相关的 Palbociclib 耐药特征”（IRPS）。在两项 CDK4/6i 加内分泌治疗的新辅助试验中，IRPS 和其他 IFN 相关特征在肿瘤对 CDK4/6i 表现出内在耐药性的患者中高度丰富。与短期治疗或未治疗的对应物相比，PalboR 衍生物显示出 IFN/STAT1 信号传导的显着激活。在原发性 ER+/HER2- 肿瘤中，lumB 亚型的 IRPS 评分显着高于 lumA 亚型，并且与免疫检查点基因表达增加、内分泌抵抗和不良预后相关。异常的 IFN 信号传导与 CDK4/6i 的内在耐药性相关。实验上，palbociclib 的获得性耐药与 IFN 通路的激活有关，需要进行更多研究来阐明其与 CDK4/6i 耐药的关系。
CDK4/6 inhibitors are highly effective against ER+/HER2- breast cancer (BC); however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i’s may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Parental BC cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen-deprivation resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes. Parental and EndoR BC lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high interferon (IFN) signaling and reduced CDK4/6i sensitivity; thus an ‘IFN-Related Palbociclib-Resistance Signature’ (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1-signaling compared to their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Aberrant IFN-signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN-pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.