Kim Eric S, Tang XiMing, Peterson Derick R, Kilari Deepak, Chow Chi-Wan, Fujimoto Junya, Kalhor Neda, Swisher Stephen G, Stewart David J, Wistuba Ignacio I, Siddik Zahid H
Department of Medicine, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Lung Cancer. 2014 Jul;85(1):88-93. doi: 10.1016/j.lungcan.2014.04.005. Epub 2014 Apr 22.
Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens.
We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls.
Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians.
To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.
铂类耐药是晚期非小细胞肺癌（NSCLC）治疗中的主要限制因素。我们之前证明，NSCLC标本中组织铂浓度低与肿瘤反应降低显著相关。此外，铜转运蛋白CTR1（铂摄取的转运蛋白）表达低与NSCLC患者接受铂类治疗后的不良临床结局相关。我们研究了NSCLC标本中组织铂浓度与CTR1表达之间的关系。
我们从MD安德森癌症中心接受新辅助铂类化疗的30例患者中，确定了已知组织铂浓度的石蜡包埋NSCLC组织块。通过免疫组织化学并设置适当对照，测定肿瘤及相邻正常肺组织标本中CTR1的表达。
在接受新辅助铂类化疗的30例患者中，组织铂浓度与肿瘤反应显著相关（P<0.001）。CTR1在NSCLC肿瘤中差异表达。与CTR1有任何表达水平的患者相比，肿瘤中CTR1表达无法检测到的部分患者铂浓度降低（P=0.058），肿瘤反应降低（P=0.016）。我们还观察到，与白种人相比，非裔美国人的CTR1表达评分显著降低（P=0.001）、组织铂浓度降低（P=0.009）以及肿瘤缩小程度降低（P=0.016）。
据我们所知，这是第一项研究CTR1在临床标本中功能的研究。CTR1表达可能是铂类药物治疗疗效所必需的，这与之前的临床前研究一致。有必要进行一项前瞻性临床试验，将CTR1开发成铂类药物的潜在生物标志物。
