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Analyses of EGFR and related molecules for individulaization of geftinib treatment for lung cancer

EGFR及相关分子分析对吉非替尼肺癌个体化治疗的影响

基本信息

批准号：
18390386
负责人：
MITSUDOMI Tetsuya
金额：
$ 10.18万
依托单位：
Aichi Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390386/
关键词：
lung caner molecular targeted therapy EGFR gene individalized therapy acquired resistance MET遺伝子遺伝子増幅遺伝子変異スプライス異常肺がん LKB1 腺癌喫煙 EGFR KRAS Peutz-Jeghers syndrome

项目摘要

Patients with pulmonary adenocarcinoma that harbors mutation of the epidermal growth factor receptor(EGFR) gene often exhibit dramatic response to EGFR-tyrosine kinase inhibitors such as gefitinib. However, its role as a predictive factor has not been established. The purpose of the present project was to analyze EGFR and related genes for individulaization of geftinib treatment for lung cancer.1) Analyses of KRAS, PIK3CA, PTEN and gefitinib sensitivity : Mutations of the KRAS gene and PIK3CA gene were detected in 9 and 2 of 78 tumors, respectively. None of 6 patients with KRAS mutations responded to gefitinib, while 2 of 2 patients with PIK3CA also had EGFR mutations and both of them responded to gefitunb. In tumors with EGFR mutations, high expressors of PIK3CA and PTEN survived for a longer period.2) Analysis of acquired resistance to gefitinib : Most of patients who initially responded gefitinib become resistant. Fourteen cases that exhibit acquired resistance were analyzed for the secondary mutations of the EGFR gene. Seven of them had T790M mutation. However, we could not find any other novel mutations. About half of the patients with acquired resistance to gefitinib was due to the secondary T790M that can be treated with the irreversible type of EGFR-TKIs of a new generation. In addition, we confirmed that the role of EGFR gene mutations as predictor of EGFR response in various settings. We also analyzed LKB1 gene status in Japanese lung cancer.Conclusion : These results can be directly translated into clinic to help select appropriate treatment strategy for patients with lung cancer.

携带表皮生长因子受体 (EGFR) 基因突变的肺腺癌患者通常对 EGFR 酪氨酸激酶抑制剂（如吉非替尼）表现出显着的反应。然而，其作为预测因素的作用尚未确定。本项目的目的是分析 EGFR 及相关基因，以实现吉非替尼治疗肺癌的个体化治疗。 1) KRAS、PIK3CA、PTEN 和吉非替尼敏感性分析：78 个肿瘤中分别检测到 9 个和 2 个肿瘤中的 KRAS 基因和 PIK3CA 基因突变。 6 名具有 KRAS 突变的患者中没有一人对吉非替尼有反应，而 2 名 PIK3CA 患者中的 2 名也有 EGFR 突变，并且两人均对吉非替尼有反应。在EGFR突变的肿瘤中，PIK3CA和PTEN的高表达者存活时间较长。2）吉非替尼获得性耐药分析：大多数最初对吉非替尼有反应的患者出现耐药。对 14 例表现出获得性耐药的病例进行了 EGFR 基因二次突变分析。其中7人有T790M突变。然而，我们找不到任何其他新的突变。大约一半对吉非替尼获得性耐药的患者是由于继发性 T790M 所致，可用新一代不可逆型 EGFR-TKI 治疗。此外，我们还证实了 EGFR 基因突变在各种情况下作为 EGFR 反应预测因子的作用。我们还分析了日本肺癌中LKB1基因的状态。结论：这些结果可以直接转化为临床，帮助肺癌患者选择合适的治疗策略。