Analyses of EGFR and related molecules for individulaization of geftinib treatment for 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）表现出显著的反应。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，为吉非替尼治疗肺癌个体化提供依据。1) KRAS、PIK3CA、PTEN及吉非替尼敏感性分析：78例肿瘤中分别检测到KRAS基因和PIK3CA基因突变9例和2例。6例KRAS突变患者对吉非替尼无应答，而2例PIK3CA患者中2例也有EGFR突变，且均对吉非替尼有应答。在EGFR突变的肿瘤中，PIK3CA和PTEN的高表达者存活时间更长。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产生耐药。对14例出现获得性耐药的患者进行了EGFR基因继发性突变分析。其中7例发生T790M突变。然而，我们没有发现任何其他新的突变。大约一半的获得性吉非替尼耐药患者是由于继发性T790M，可以用新一代不可逆型EGFR-TKIs治疗。此外，我们证实了EGFR基因突变在各种情况下作为EGFR反应的预测因子的作用。我们还分析了LKB1基因在日本肺癌中的状态。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。

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.