Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

The epidermal growth factor receptor inhibitor cetuximab is the only oncogene-targeted agent that has been FDA approved for the treatment of head and neck squamous cell carcinoma (HNSCC). Currently, there are no biomarkers used in the clinic to predict which HNSCC tumors will respond to cetuximab, and even in tumors that regress with treatment, acquired resistance occurs in the majority of cases. Though a number of mechanisms of acquired resistance to cetuximab have been identified in preclinical studies, no therapies targeting these resistance pathways have yet been effectively translated into the clinic. To address this unmet need, we examined the role of the cytokine interleukin 6 (IL-6) in acquired cetuximab resistance in preclinical models of HNSCC. We found that IL-6 secretion was increased in PE/CA-PJ49 cells that had acquired resistance to cetuximab compared to the parental cells from which they were derived. However, addition of exogenous IL-6 to parental cells did not promote cetuximab resistance, and inhibition of the IL-6 pathway did not restore cetuximab sensitivity in the cetuximab-resistant cells. Further examination of the IL-6 pathway revealed that expression of IL6R, which encodes a component of the IL-6 receptor, was decreased in cetuximab-resistant cells compared to parental cells, and that treatment of the cetuximab-resistant cells with exogenous IL-6 did not induce phosphorylation of signal transducer and activator of transcription 3, suggesting that the IL-6 pathway was functionally impaired in the cetuximab-resistant cells. These findings demonstrate that, even if IL-6 is increased in the context of cetuximab resistance, it is not necessarily required for maintenance of the resistant phenotype, and that targeting the IL-6 pathway may not restore sensitivity to cetuximab in cetuximab-refractory HNSCC.表皮生长因子受体抑制剂西妥昔单抗（cetuximab）是目前唯一获美国食品药品监督管理局（FDA）批准用于治疗头颈部鳞状细胞癌（head and neck squamous cell carcinoma, HNSCC）的靶向致癌基因药物。当前临床尚无生物标志物可预测哪些头颈部鳞状细胞癌肿瘤会对西妥昔单抗产生应答，且即便经治疗后肿瘤出现退缩，多数病例仍会发生获得性耐药。尽管临床前研究已明确多种西妥昔单抗获得性耐药的机制，但尚未有针对这些耐药通路的疗法被成功转化至临床应用。为解决这一未被满足的临床需求，我们在头颈部鳞状细胞癌的临床前模型中探究了细胞因子白细胞介素6（interleukin 6, IL-6）在西妥昔单抗获得性耐药中的作用。研究发现，与亲本细胞相比，获得西妥昔单抗耐药性的PE/CA-PJ49细胞的IL-6分泌水平升高。不过，向亲本细胞添加外源性IL-6并不会使其产生西妥昔单抗耐药性，而抑制IL-6通路也未能恢复耐药细胞对西妥昔单抗的敏感性。进一步对IL-6通路的分析显示，与亲本细胞相比，西妥昔单抗耐药细胞中编码IL-6受体组分的IL6R基因表达下调；且向耐药细胞添加外源性IL-6并不会诱导信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3）的磷酸化，这表明IL-6通路在西妥昔单抗耐药细胞中存在功能缺陷。上述研究结果表明，即便西妥昔单抗耐药环境中IL-6水平升高，其也未必是维持耐药表型所必需的，且靶向IL-6通路或许无法恢复西妥昔单抗难治性头颈部鳞状细胞癌对西妥昔单抗的敏感性。