Ready Neal
Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
Semin Oncol. 2005 Apr;32(2 Suppl 3):S35-41. doi: 10.1053/j.seminoncol.2005.03.008.
Epidermal growth factor receptor 1 (EGFR 1 ) is a 170-kd glycoprotein that plays many roles in the growth of non-small cell lung cancer (NSCLC). There are four known receptors in the EGFR family. Binding of a ligand such as epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) causes EGFR to undergo a conformational change leading to autophosphorylation of EGFR and activation of the EGFR growth factor pathway. The protein products of the genes that are then expressed increase cell proliferation and angiogenesis and inhibit programmed cell death. EGFR is expressed in 40% to 80% of NSCLC. EGFR tyrosine kinase activity can be inhibited by antibody therapy, such as cetuximab, against the extracellular domain of EGFR or small-molecule therapy, such as gefitinib or erlotinib that blocks the adenosine triphosphate (ATP) binding site of the cytoplasmic domain. Both forms of EGFR inhibition have single-agent antitumor activity against previously treated NSCLC. Interestingly, EGFR expression does not correlate with response to EGFR inhibition therapy. Increased likelihood of responding to small-molecule therapy is associated with female gender, never smoking, adenocarcinoma, and acquired mutations of the EGFR ATP binding site in tumor cells. In previously treated NSCLC, the small-molecule erlotinib improved both quality of life and median survival as a single agent compared with best supportive care. Southwest Oncology Group 0023 is a large, phase III, randomized trial comparing concurrent chemoradiotherapy and consolidation docetaxel with or without maintenance small-molecule therapy with gefitinib. There is also strong preclinical evidence that EGFR inhibition is additive or synergistic with radiotherapy in NSCLC. In locally advanced head and neck cancer, the addition of cetuximab antibody therapy to radiation increased median survival from 28 to 54 months. Cancer and Leukemia Group B 30106 and a multi-institutional Australian phase I trial have shown that gefitinib can be added to concurrent chemoradiotherapy for stage III NSCLC without excessive toxicity. A phase I trial at the University of Chicago (Chicago, IL) has evaluated erlotinib with concurrent chemoradiotherapy in stage III NSCLC. Radiation Therapy Oncology Group 0324 is an on-going phase II trial studying cetuximab and concurrent chemoradiotherapy in stage III NSCLC.
表皮生长因子受体1（EGFR 1）是一种170千道尔顿的糖蛋白，在非小细胞肺癌（NSCLC）的生长中发挥多种作用。EGFR家族中有四种已知受体。表皮生长因子（EGF）或转化生长因子-α（TGF-α）等配体的结合会导致EGFR发生构象变化，进而导致EGFR自身磷酸化并激活EGFR生长因子途径。随后表达的基因的蛋白质产物会增加细胞增殖和血管生成，并抑制程序性细胞死亡。40%至80%的NSCLC中表达EGFR。EGFR酪氨酸激酶活性可通过针对EGFR细胞外结构域的抗体疗法（如西妥昔单抗）或小分子疗法（如吉非替尼或厄洛替尼，其可阻断细胞质结构域的三磷酸腺苷（ATP）结合位点）来抑制。两种形式的EGFR抑制对先前治疗过的NSCLC均具有单药抗肿瘤活性。有趣的是，EGFR表达与EGFR抑制疗法的反应无关。对小分子疗法有更高反应可能性与女性、从不吸烟、腺癌以及肿瘤细胞中EGFR ATP结合位点的获得性突变有关。在先前治疗过的NSCLC中，与最佳支持治疗相比，小分子厄洛替尼作为单药可改善生活质量和中位生存期。西南肿瘤协作组0023是一项大型III期随机试验，比较同步放化疗和巩固多西他赛联合或不联合吉非替尼维持小分子疗法。也有强有力的临床前证据表明，在NSCLC中EGFR抑制与放疗具有相加或协同作用。在局部晚期头颈癌中，放疗联合西妥昔单抗抗体疗法可使中位生存期从28个月延长至54个月。癌症与白血病B组30106以及一项澳大利亚多机构I期试验表明，吉非替尼可添加到III期NSCLC的同步放化疗中且无过度毒性。芝加哥大学（伊利诺伊州芝加哥）的一项I期试验评估了厄洛替尼与III期NSCLC同步放化疗联合应用的情况。放射治疗肿瘤学组0324是一项正在进行的II期试验，研究西妥昔单抗与III期NSCLC同步放化疗联合应用的情况。
