A phosphoarray platform is capable of personalizing kinase inhibitor therapy in head and neck cancers.
A phosphoarray platform is capable of personalizing kinase inhibitor therapy in head and neck cancers.
复制标题
磷酸阵列平台能够对头颈癌进行个性化激酶抑制剂治疗。
DOI：
10.1002/ijc.31045
复制
发表时间：
2018
影响因子：
6.4
通讯作者：
Hayman,MichaelJ
中科院分区：
文献类型：
--
作者：
Klinghammer,Konrad;Keller,James;George,Jonathan;Hoffmann,Jens;Chan,EdwardL;Hayman,MichaelJ
酪氨酸激酶抑制剂是癌症的有效治疗方法。了解驱动潜在癌症的特定激酶突变体可以预测对这些抑制剂的治疗反应。因此，目前的个性化癌症治疗方案涉及对肿瘤进行基因分型以寻找各种驱动突变，随后针对其肿瘤表达相应驱动突变的患者个体化酪氨酸激酶抑制剂。虽然这种方法在发现已知驱动突变时有效，但其局限性在于依赖驱动突变作为响应的预测因子。为了补充基因型方法，我们假设磷酸阵列平台同样能够个性化激酶抑制剂治疗。我们选择头颈部鳞状细胞癌作为癌症模型来验证我们的假设。使用受体酪氨酸激酶磷酸化阵列，我们确定了49种不同的酪氨酸激酶受体在5种不同的头颈癌细胞系的磷酸化谱。基于这些结果，我们测试了细胞系对相应激酶抑制剂治疗的反应。我们发现，这种磷酸化阵列准确地告知激酶抑制剂的细胞系的反应概况。接下来，我们确定了39个头颈癌患者来源的异种移植物的磷酸化谱。我们发现，在没有磷酸化ErbB2的异种移植物中，磷酸化EGFR信号的缺失预示着对西妥昔单抗治疗的原发性耐药。同时，在具有磷酸化EGFR的异种移植物中ErbB2信号传导的缺失与对西妥昔单抗应答的可能性更高相关。总之，磷酸阵列技术有潜力成为个性化癌症治疗的新诊断平台。
Tyrosine kinase inhibitors are effective treatments for cancers. Knowing the specific kinase mutants that drive the underlying cancers predict therapeutic response to these inhibitors. Thus, the current protocol for personalized cancer therapy involves genotyping tumors in search of various driver mutations and subsequently individualizing the tyrosine kinase inhibitor to the patients whose tumors express the corresponding driver mutant. While this approach works when known driver mutations are found, its limitation is the dependence on driver mutations as predictors for response. To complement the genotype approach, we hypothesize that a phosphoarray platform is equally capable of personalizing kinase inhibitor therapy. We selected head and neck squamous cell carcinoma as the cancer model to test our hypothesis. Using the receptor tyrosine kinase phosphoarray, we identified the phosphorylation profiles of 49 different tyrosine kinase receptors in five different head and neck cancer cell lines. Based on these results, we tested the cell line response to the corresponding kinase inhibitor therapy. We found that this phosphoarray accurately informed the kinase inhibitor response profile of the cell lines. Next, we determined the phosphorylation profiles of 39 head and neck cancer patient derived xenografts. We found that absent phosphorylated EGFR signal predicted primary resistance to cetuximab treatment in the xenografts without phosphorylated ErbB2. Meanwhile, absent ErbB2 signaling in the xenografts with phosphorylated EGFR is associated with a higher likelihood of response to cetuximab. In summary, the phosphoarray technology has the potential to become a new diagnostic platform for personalized cancer therapy.