Kettner Nicole M, Vijayaraghavan Smruthi, Durak Merih Guray, Bui Tuyen, Kohansal Mehrnoosh, Ha Min Jin, Liu Bin, Rao Xiayu, Wang Jing, Yi Min, Carey Jason P W, Chen Xian, Eckols T Kris, Raghavendra Akshara S, Ibrahim Nuhad K, Karuturi Meghan Sri, Watowich Stephanie S, Sahin Aysegul, Tweardy David J, Hunt Kelly K, Tripathy Debu, Keyomarsi Khandan
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2019 Jul 1;25(13):3996-4013. doi: 10.1158/1078-0432.CCR-18-3274. Epub 2019 Mar 13.
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.
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.
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.
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.
细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂目前与内分泌疗法联合用于治疗晚期激素受体阳性、人表皮生长因子受体2阴性乳腺癌。尽管与单纯内分泌疗法相比，这种治疗使疾病进展时间加倍，但约25%-35%的患者无反应，且几乎所有患者最终都会产生耐药性。识别对CDK4/6抑制的耐药机制对于制定替代治疗策略至关重要。
以逐步递增剂量的方式生成帕博西尼耐药细胞（MCF-7和T47D）。对耐药细胞和亲本（敏感）细胞都进行了全外显子测序、全基因组表达分析和蛋白质组分析。从机制和药理学方面评估通路改变。在接受帕博西尼治疗的乳腺癌患者疾病进展时的肿瘤样本中检测改变通路的生物标志物。
帕博西尼耐药细胞对其他CDK4/6抑制剂具有交叉耐药性，并且对内分泌疗法（雌激素受体下调）也耐药。耐药细胞中白细胞介素6/信号转导和转录激活因子3（IL6/STAT3）通路被诱导，而DNA修复和雌激素受体通路下调。联合抑制STAT3和聚（二磷酸腺苷-核糖）聚合酶（PARP）可显著增加耐药细胞的死亡。对在帕博西尼治疗期间疾病进展的乳腺癌患者的配对肿瘤样本进行雌激素受体、DNA修复和IL6/STAT3信号转导失调检测，结果显示与治疗前肿瘤样本相比，这些通路均发生了改变。
帕博西尼耐药在细胞系和患者样本中诱导内分泌耐药、雌激素受体下调以及IL6/STAT3和DNA损伤反应通路改变。使用特异性STAT3抑制剂联合PARP抑制剂靶向IL6/STAT3活性和DNA修复缺陷可有效治疗对帕博西尼的获得性耐药。
