Combined Inhibition of STAT3 and DNA Repair in Palbociclib-Resistant ER-Positive Breast Cancer
Combined Inhibition of STAT3 and DNA Repair in Palbociclib-Resistant ER-Positive Breast Cancer
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DOI：
10.1158/1078-0432.ccr-18-3274
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发表时间：
2019-07-01
影响因子：
11.5
通讯作者：
Keyomarsi, Khandan
中科院分区：
文献类型：
--
作者：
Kettner, Nicole M.;Vijayaraghavan, Smruthi;Keyomarsi, Khandan
目的：细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂目前与内分泌治疗联合用于治疗晚期激素受体阳性、HER2阴性乳腺癌。尽管与单独内分泌治疗相比，这种治疗使进展时间加倍，但约 25%-35% 的患者没有反应，并且几乎所有患者最终都会产生耐药性。辨别 CDK4/6 抑制的耐药机制对于设计替代治疗策略至关重要。实验设计：以逐步剂量递增的方式产生 Palbociclib 耐药细胞（MCF-7 和 T47D）。在耐药细胞和亲本（敏感）细胞中进行了全外显子组测序、全基因组表达分析和蛋白质组分析。从机制和药理学角度评估途径改变。在接受 Palbociclib 治疗的乳腺癌患者（其疾病在治疗过程中出现进展）的肿瘤样本中检查了通路改变的生物标志物。结果：Palbociclib 耐药细胞对其他 CDK4/6 抑制剂具有交叉耐药性，并且对内分泌治疗（雌激素受体下调）也具有耐药性。 IL6/STAT3 通路被诱导，而 DNA 修复和雌激素受体通路在耐药细胞中被下调。 STAT3 和 PARP 的联合抑制显着增加了耐药细胞的细胞死亡。对接受 Palbociclib 治疗后病情进展的乳腺癌患者的匹配肿瘤样本进行了雌激素受体失调、DNA 修复和 IL6/STAT3 信号传导的检查，结果显示，与治疗前的肿瘤样本相比，这些途径均发生了改变。 结论：Palbociclib 耐药会诱导细胞系和患者样本中的内分泌抵抗、雌激素受体下调以及 IL6/STAT3 和 DNA 损伤反应途径的改变。使用特定的 STAT3 抑制剂与 PARP 抑制剂联合针对 IL6/STAT3 活性和 DNA 修复缺陷，可以有效治疗对帕博西尼的获得性耐药。
Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are currently used in combination with endocrine therapy to treat advanced hormone receptor-positive, HER2-negative breast cancer. Although this treatment doubles time to progression compared with endocrine therapy alone, about 25%-35% of patients do not respond, and almost all patients eventually acquire resistance. Discerning the mechanisms of resistance to CDK4/6 inhibition is crucial in devising alternative treatment strategies.Experimental Design: Palbociclib-resistant cells (MCF-7 and T47D) were generated in a step-wise dose-escalading fashion. Whole-exome sequencing, genome-wide expression analysis, and proteomic analysis were performed in both resistant and parental (sensitive) cells. Pathway alteration was assessed mechanistically and pharmacologically. Biomarkers of altered pathways were examined in tumor samples from patients with palbociclib-treated breast cancer whose disease progressed while on treatment.Results: Palbociclib-resistant cells are cross-resistant to other CDK4/6 inhibitors and are also resistant to endocrine therapy (estrogen receptor downregulation). IL6/STAT3 pathway is induced, whereas DNA repair and estrogen receptor pathways are downregulated in the resistant cells. Combined inhibition of STAT3 and PARP significantly increased cell death in the resistant cells. Matched tumor samples from patients with breast cancer who progressed on palbociclib were examined for deregulation of estrogen receptor, DNA repair, and IL6/STAT3 signaling, and results revealed that these pathways are all altered as compared with the pretreatment tumor samples.Conclusions: Palbociclib resistance induces endocrine resistance, estrogen receptor downregulation, and alteration of IL6/STAT3 and DNA damage response pathways in cell lines and patient samples. Targeting IL6/STAT3 activity and DNA repair deficiency using a specific STAT3 inhibitor combined with a PARP inhibitor could effectively treat acquired resistance to palbociclib.