Fang Wenfeng, Huang Yihua, Gu Weiguang, Gan Jiadi, Wang Wenjing, Zhang Shiyue, Wang Kai, Zhan Jianhua, Yang Yunpeng, Huang Yan, Zhao Hongyun, Zhang Li
Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Medical Oncology, People's Hospital of Nanhai District, Foshan, China.
Transl Lung Cancer Res. 2020 Aug;9(4):1258-1267. doi: 10.21037/tlcr-20-141.
Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance.
A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor.
Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6).
Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.
包括PI3K-AKT-mTOR通路异常激活在内的多种机制已被证明会导致非小细胞肺癌（NSCLC）对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）产生获得性耐药。在本研究中，我们调查了EGFR-TKIs治疗进展后NSCLC患者中激活的PI3K通路的基因组特征，以及同时靶向EGFR和PI3K通路是否能克服耐药性。
回顾了总共605例有EGFR TKI治疗史的NSCLC病例，其中324例携带EGFR突变的患者被证实至少对一种EGFR TKI治疗进展，最终纳入研究。在TKI治疗进展时收集肿瘤组织或血液样本进行二代测序（NGS）。回顾性收集6例PI3K通路同时发生突变的EGFR突变患者，以评估EGFR TKI联合mTOR抑制剂依维莫司的疗效。
49例（14.9%）对EGFR TKIs耐药的患者在PI3K通路中至少有一个基因变异。分别在31例（9.5%）、18例（5.5%）和3例（0.9%）患者中检测到PIK3CA、PTEN和AKT1变异。在不同EGFR突变（EGFR外显子19缺失突变/EGFR L858R/罕见EGFR突变）的患者以及对不同EGFR TKIs耐药的患者中，PI3K通路改变的分布没有显著差异。对于接受依维莫司和EGFR-TKI治疗的患者，5例（5/6，83.3%）病情稳定（SD），1例（1/6，16.7%）未获得疾病控制。中位无进展生存期（PFS）为2.1个月（95%置信区间，1.35-4.3个月，范围，0.9-4.4个月）。最常见的不良事件是口腔溃疡（6/6）、皮疹（1/6）。
我们的研究表明，在EGFR-TKI耐药患者中至少14.9%的患者PI3K通路被激活。EGFR-TKIs联合依维莫司在PI3K通路异常的EGFR突变NSCLC患者中显示出有限的抗肿瘤活性。
