A pilot study of preoperative gefitinib for early-stage lung cancer to assess intratumor drug concentration and pathways mediating primary resistance.
A pilot study of preoperative gefitinib for early-stage lung cancer to assess intratumor drug concentration and pathways mediating primary resistance.
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DOI：
10.1097/jto.0b013e3181f38f70
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Becker A
中科院分区：
文献类型：
--
作者：
Haura EB;Sommers E;Song L;Chiappori A;Becker A
靶向药物如酪氨酸激酶抑制剂已在临床前系统以及晚期患者中进行了广泛研究。与血浆相比，对肿瘤中发现的激酶抑制剂水平知之甚少。类似地，抑制剂对基于患者的材料中的肿瘤信号通路的影响尚不清楚。为了探讨这些问题，我们进行了一项试验，在早期非小细胞肺癌（NSCLC）患者中进行了一个简短的术前吉非替尼（一种表皮生长因子受体（EGFR）抑制剂）疗程。患有早期NSCLC的患者在手术切除之前接受了4周的吉非替尼250 mg/天。治疗前和治疗后的CT扫描和PET扫描用于评估临床反应。评价吉非替尼和手术毒性。评价肿瘤组织的吉非替尼水平，并与血浆吉非替尼水平进行比较。在手术切除的肿瘤组织中检测了包括EGFR、Stat3、ERK和AKT的活化信号分子。23例患者参与了研究，均接受了肿瘤手术切除。没有出现与吉非替尼或手术的已知作用无关的毒性。22例患者病情稳定，1例肿瘤大小进展。与PET反应和CT反应无关。吉非替尼的肿瘤水平比血浆水平高近40倍，表明吉非替尼的潜在肿瘤浓度。酪氨酸磷酸化的Stat3在手术切除的肿瘤组织中丰富，表明在体内原发性耐药中的潜在作用。该研究证实了先前的临床前观察结果，即肿瘤组织浓缩吉非替尼。持续性Stat3可能导致体内对EGFR抑制剂的原发性耐药性。
Targeted agents such as tyrosine kinase inhibitors have been extensively studied in pre-clinical systems as well as in advanced stage patients. Little is known about levels of kinase inhibitors found in tumors as opposed to plasma. Similarly, effects of inhibitors on tumor signaling pathways in patient-based materials is unclear. To explore these questions, we conducted a trial of a brief course of pre-operative gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, in early stage non-small cell lung cancer (NSCLC). Patient with early stage NSCLC received four weeks of gefitinib 250 mg daily prior to surgical resection. Pre- and post-treatment CT scans and PET scans were used to assess clinical response. Geftinib and surgical toxicity was evaluated. Tumor tissue was evaluated for gefitinib levels and was compared to plasma gefitinib levels. Activated signaling molecules including EGFR, Stat3, ERK, and AKT were examined in surgically resected tumor tissue. 23 patients participated in the study and all had surgical resection of tumors. No toxicities unrelated to known effects of gefitinib or surgery were encountered. 22 patients had stable disease and one had progression in tumor size. There was no correlation with PET response and CT response. Tumor levels of gefitinib were nearly 40-fold higher than plasma levels indicating potential tumor concentration of gefitinib. Tyrosine phosphorylated Stat3 was abundant in the surgically resected tumor tissue indicating potential role in primary resistance in vivo. This study confirms previous preclinical observations that tumor tissues concentrate gefitinib. Persistent Stat3 may be leading to primary resistance to EGFR inhibitors in vivo.